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Review

Effects and mechanisms of actions of phytochemicals on Alzheimer’s disease neuropathology

Richard E. Hartman1,*,David M. Ross1
1
Department of Psychology, Loma Linda University, 11130 Anderson Street. Loma Linda, California 92350
DOI: 10.2741/E824 Volume 10 Issue 2, pp.300-333
Published: 01 January 2018
(This article belongs to the Special Issue )
*Corresponding Author(s):  
Richard E. Hartman
E-mail:  
behavioralneuroscience@gmail.com
Abstract

Alzheimer’s disease affects millions of people, yet, there are only a limited number approaches for it pharmacological treatment. Thus, identifying factors that decrease the risk of developing Alzheimer’s disease is of paramount importance. A growing body of epidemiological and experimental evidence suggests that dietary fruits and vegetables have neuroprotective effects against the harmful effects of oxidative stress, neuroinflammation, and aging. These effects are mediated by various phytochemical compounds found in plants that exhibit antioxidant, anti-inflammatory, and other beneficial properties. This review addresses epidemiological and experimental evidence for the effects and potential mechanisms of several commonly consumed phytochemicals on neuropathology and outcomes of Alzheimer’s disease. Based on available evidence, we suggest that regular consumption of bioactive phytochemicals from a variety of fruits and vegetables attenuates age- and insult-related neuropathology in Alzheimer’s disease.

Key words

Alzheimer’s Disease, Phytochemicals, Neuroprotection, Alzheimer’s Disease Prevention, Review

2. Introduction

Phytochemicals are compounds produced by plants, some of which (e.g., phenols, terpenes, and organosulfurs) result in pigmentation, odors, and irritants that can protect the plant from internal (e.g., metabolic) insults like protein overexpression and free radical reactive oxygen species (ROS), and external (e.g., environmental) insults like predators, pathogens, ultraviolet radiation, and other threats to the plants’ survival. Consumption of plants that produce these phytochemicals seems to produce health benefits for humans mediated by modulating several biological pathways, including inflammatory processes, neuronal cell death (apoptosis), neurogenesis, neurotransmission, and enzyme function (1, 2). Many of these pathways have a direct effect on the development of Alzheimer’s disease (AD) and other types of age-related neuropathology. This review will provide a brief overview of AD etiology, followed by an outline of dietary phytochemicals that have been shown to affect age- and AD-related neuropathology and functional outcomes.

3. Alzheimer’s disease neuropathology

Recent prevalence rates suggest that over 5 million Americans currently have AD (3), which is behaviorally characterized by a presentation of memory, motor, language, and executive dysfunction. The neuropathological markers of AD were originally thought to be limited to the formation of amyloid plaques surrounding neurons and the presence of neurofibrillary tangles (NFTs) of tau protein inside neurons. However, in recent years, the significance of mitochondrial dysfunction, neuroinflammation, astrogliosis, microglial activation, synaptic loss, neuronal damage, apoptosis, disruption of blood brain barrier (BBB) permeability, bacterial and viral infections, and intestinal microbiota have all been identified as significant contributors to AD neuropathology (4-19).

Plaque accumulation has been identified in the medial temporal lobe, particularly the hippocampus and entorhinal cortex, prior to the emergence of behavioral symptoms. These structures have been implicated in learning and memory processes, which explains the cognitive impairments associated with AD. The extracellular plaques consist mainly of amyloid-beta (Aβ) peptides cleaved from larger amyloid precursor proteins (APP) by γ-secretase and β-secretase enzymes. The increasing concentration of extracellular Aβ monomers gradually results in their polymerization into diffuse aggregates and eventually dense-core amyloid plaques (20). Other proteins (e.g., apolipoproteins) and non-proteins (e.g., metals, hemes, and ROS) have also been found within the plaques (21-24). An age related increase in cortical and subcortical amyloid plaque levels is one of the most salient AD biomarkers (25). NFTs, another prevalent AD biomarker, are damaged tau-based microtubules that disrupt intracellular transport mechanisms. Typically, these damaged neurons are found in areas with higher Aβ concentrations. Eventually, these damaged neurons are unable to function properly, leading to neuronal death. One current hypothesis for the etiology of AD is that the gradual accumulation of Aβ between the neurons initiates inflammatory and oxidative processes that lead to the formation of synaptic loss, NFTs, and neurodegeneration, particularly in neurons that use acetylcholine and glutamate (20, 26, 27).

Aβ neurotoxicity has been demonstrated in hippocampal cell cultures (28), and the deleterious effects of Aβ deposition on synaptic functioning in the brain have been demonstrated using long-term potentiation (LTP), an in vitro model of learning and memory (29-31). Aβ has also been shown to induce hypersensitivity to excitotoxicity (i.e., damage caused by dysfunctional firing of glutamate) and oxidative stress in vitro (32, 33). Furthermore, the formation of Aβ-heme peroxidase complexes within Aβ plaques begins a neuroinflammatory cascade leading to release of ROS and damage to muscarinic acetylcholine receptors within the brain (34, 35). Importantly, these damaging effects can be ameliorated by dietary antioxidants (36-38). Although the accumulation of extracellular Aβ plaques is a prominent feature of the AD brain, synaptic loss within and surrounding the plaques may be a better predictor of the cognitive dysfunction seen in AD than the total amount of Aβ plaque deposition (39, 40). Individuals may be biologically more or less susceptible to neuronal buildup of Aβ, which may explain why the overall Aβ plaque burden is generally not a direct indicator of AD symptom severity (41, 42).

Although it is currently unclear whether Aβ deposition is a primary cause of the neurodegeneration and behavioral deficits associated with AD, the gradual accumulation of Aβ in the brain appears to be associated with progressive oxidative stress and various harmful downstream effects. Oxidative stress associated with AD is believed to be partly responsible for damage to neuronal structures that contributes to functional deficits and ultimately neuronal death. Furthermore, experimental evidence suggests that manipulating levels of Aβ deposition in the brain can influence the emergence of behavioral deficits.

For example, accelerated Aβ plaque accumulation tends to increase the risk of developing behavioral deficits associated with AD (i.e., learning and memory problems). Pathophysiological conditions that accelerate Aβ accumulation in the brain have been shown to increase the risk of developing AD. These conditions include Down syndrome, which is characterized by an overproduction of APP in the brain, leading to elevated Aβ production and deposition. Individuals with Down syndrome are typically diagnosed with some form of dementia by approximately 50 years of age (43-45). Additionally, several inheritable mutations in the genes for APP or γ-secretase lead to elevated APP production and Aβ deposition in the brain and an earlier onset of AD (46-48). Identification of these genes has resulted in the development of transgenic rodent models of AD that express high levels of human APP and develop age-related neuropathology and cognitive deficits congruent with Aβ aggregation and deposition in the brain (49-52). Transgenic rodent models of AD focused on Aβ plaque development appear to mirror the behavioral hallmarks of AD seen in humans diagnosed with AD (53). Additionally, in vivo imaging shows that Aβ plaques can aggregate rapidly in transgenic rodent brains, and that markers of neurodegeneration around these Aβ plaques develop quickly (54, 55). Finally, neuroinflammatory processes and oxidative stress can induce accumulation of APP and Aβ in the brain, increasing the risk for developing AD. Common sources of these insults include traumatic brain injury, stroke, chronic low-level hypoxia (e.g., due to breathing problems), the “Western” diet (56-66), and (importantly) the accumulation of Aβ. Oxidative stress is a common component of all brain injury and can induce further Aβ accumulation, initiating a harmful cycle of progressive oxidative and inflammatory load in the brain. (67, 68).

In addition to the observation that accelerating Aβ accumulation can increase the risk of developing AD and associated behavioral deficits, experiments with transgenic rodent models of Aβ plaque accumulation in the brain have shown that reducing Aβ levels in the brain can improve behavioral outcomes. These experiments include systemic treatments with monoclonal anti-Aβ antibodies and dietary manipulations that prevent, or in some cases reverse, the neuropathology and behavioral deficits associated with AD (53, 69-79). Reducing oxidative load in the brain is another pathway to improving cognitive function in Aβ transgenic rodent models without reducing Aβ levels (80-82). These findings suggest that Aβ contributes to the process of oxidative stress overload that gradually impacts the function of brain structures that mediate learning and memory.

In summary, AD is associated with an abnormal buildup of Aβ plaques in the brain, which ultimately induces even greater Aβ accumulation in the brain. This “amyloid cascade” process creates a damaging cycle of neurodegenerative decline, including the formation of NFTs, synaptic dysfunction and loss, excitotoxicity and apoptosis (83-86). Current pharmacological approaches for treating AD have focused on stabilizing glutamatergic activity by blocking NMDA channels (e.g., memantine) and inhibiting acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine and has been shown to induce Aβ aggregation (e.g., galantamine, tacrine, donepezil, and rivastigmine). NMDA antagonists can slightly slow the progression of AD symptoms and may reduce the susceptibility of neurons to excitotoxic degeneration. AChE inhibitors have been shown in animal experiments to slow AChE’s promotion of Aβ aggregation. Nevertheless, pharmacological treatments that target glutamate and acetylcholine have ultimately yielded disappointing results. Other experimental approaches that have yielded mixed results. Active and passive Aβ immunotherapies in transgenic mouse models of AD have yielded promising results, even in the absence of significant reductions in Aβ burden (87-89). Human immunotherapy treatment has been more problematic, due to significant toxicity and tolerability concerns (90-95). Although theses pharmacological failures have raised questions about the amyloid cascade hypothesis of AD, it has also been proposed that Aβ may initiate a multi-faceted pathogenic cascade that causes AD, rather than acting as the sole causative factor (83, 96, 97). These downstream processes include tau aggregation, extracellular senile plaque formations, mitochondrial dysfunction, neuroinflammatory processes, blood brain barrier (BBB) permeability disruption, and gut microbiome disturbances (6, 7, 98-105). Despite the lack of significant progress towards effective pharmacological interventions for AD, mounting epidemiological and experimental evidence indicates that diet and other sources of bioactive phytochemicals can significantly decrease the risk of developing AD neuropathology and symptoms by several potential mechanisms (106-109).

4. Phytochemicals and Alzheimer’s disease

A growing body of literature demonstrates that several bioactive phytochemical compounds, including vitamins (e.g. tocopherols and folic acid) and other organic compounds (e.g. phenols, terpenes, and organosulfurs) can affect aspects of the AD disease process. Potential mechanisms for these effects include antioxidant / anti-inflammatory properties and modulation of Aβ concentrations and toxicity. Indeed, several pharmacological interventions of interest in AD stem from traditional herbal medicines. For example, the AChE inhibitor galantamine is derived from daffodil plants, and the anti-inflammation drug aspirin is derived from salicylic acid, a polyphenol found in the bark of willow trees. Both phytochemicals have garnered interest in the treatment of AD. Additionally, the role of the gut microbiome has been of increasing interest in studying the activity and mechanisms of dietary phytochemical compounds. Approximately 100 trillion diverse species of very metabolically active bacteria line the intestinal tract and have a strong influence (both pro- and anti-) on neuroinflammation, neuromodulation, and neurotransmission in the brain and periphery. The role of the potentially neurotoxic and proinflammatory microbial activations and their relationship to age-related amyloidogenesis and neurodegeneration are of increasing interest (110, 111). In addition to the gut’s role in the disease process of AD, its microbiome is also highly implicated in the bioavailability and bioactivation of dietary phytochemicals. It has been shown that 5-10% of dietary phytochemicals are absorbed initially. The remaining phytochemicals reach the colon, where they undergo extensive metabolizing by microbiota. Although the metabolic pathways and the molecular targets are not well understood, the intestinal microbiome’s breakdown of dietary polyphenols may enhance their beneficial properties (112-116). Recent studies of the pharmacokinetic activity of several microbiome-produced polyphenol metabolites found that many of them reached the brain in statistically significant concentrations (105, 114, 117). The following sections provide a survey of the epidemiological and experimental evidence for the effects of various plants, phytochemicals, and their metabolites on AD processes.

4.1. Epidemiological evidence

Several studies have demonstrated that regular consumption of a variety of fruits and vegetables can decrease the risk for developing AD and slow its progression. For example, a large Swedish study collected dietary questionnaires from young adults approximately 40 years before regular cognitive screenings began in older age. It was found that higher fruit and vegetable consumption in earlier life was associated with a decreased risk of dementia and AD (118). Similarly, a study of Irish adults, aged 64-93 years, found that consuming more fruits and vegetables was associated with significantly better overall cognitive functioning (119). However, another study reported that consumption of dietary tocopherols (isoforms of vitamin E), vitamin C, P-carotene, and tea were not correlated with the risk of developing AD (120).

Additionally, epidemiological evidence that isolated phytochemicals can affect AD remains elusive. A study of older American adults to identify dementia incidence and AD diagnoses found that the use of vitamins C and E alone or in combination did not reduce AD or dementia incidence after a 5-year follow-up (121). Another study examining the effects of vitamin E supplementation in mild cognitive impairment (MCI) and AD found no evidence that it was beneficial (122). However, one study of older Chinese adults reported that lower α-tocopherol levels were found in those diagnosed with MCI than in healthy controls (123), and another recent study found that higher dietary intake of vitamins A, C, and E is associated with protection from AD (124). Nevertheless, the evidence suggests that acquiring vitamins through a varied diet of vitamin rich foods may provide more protection from AD than the use of vitamin supplementation. A recent study of elderly French adults examined the association between dietary vitamin B consumption and long-term incidence of dementia. Higher intake of dietary vitamin B reduced the risk of dementia with an approximately 50% lower risk for individuals consuming the highest amounts compared to the lowest consumers (125).

Furthermore, growing epidemiological evidence suggests that dietary omega-3 fatty acids, most commonly found in flax, nuts, algae, and oil from fish that eat algae, may protect against developing AD (126-130). The so-called “Mediterranean” diet, which is characterized by regular consumption of foods with high fatty acid content from fish, nuts, and oils, has been of increasing interest, due to the growing body of evidence that it is associated with several health benefits, including a reduced incidence of AD. Consumption of dietary fatty acids appears to explain a portion of the diet’s neuroprotective characteristics (131), and several epidemiological studies have demonstrated that diets supplemented with olive oil and/or nuts are associated with improved cognitive function in older adults (127, 132, 133).

Other sources of bioactive phytochemicals include colorful, flavorful, and aromatic spices. These spices often contain high concentrations of various phenols, terpenes, and organosulfurs. For example, a study of elderly adults showed that those whose diets included curry performed significantly better on neuropsychological tests of cognitive performance (134). This spice mix includes turmeric, a bright yellow root that contains a high concentration of the polyphenol curcumin. Light to moderate wine consumption has also been associated with a reduced risk for AD, although it remains unclear whether the effect is due to grape polyphenols (e.g., resveratrol) or ethanol (which itself is derived from plants) (135-137).

Phytochemicals can also be consumed by other methods other than diet. For example, smoking tobacco was previously thought to possibly offer protection from Aβ deposition and the occurrence of AD. This was in large part due to postmortem examinations of the brains of AD that showed significantly lower levels of Aβ in the entorhinal cortex of smokers (138). However, recent epidemiological studies have identified smoking as a risk factor for the development of AD (139). A large community study of adults in the US found that older individuals who currently smoke are more likely to develop AD than those who never smoked. Given that experimental evidence of nicotine administered in animal models of AD suggests that nicotine may be neuroprotective (see section 4.2.6.2.), it appears likely that the act of smoking tobacco, rather than consumption of nicotine itself, increases the risk for developing AD, despite evidence of decreased postmortem Aβ in smoker’s brains.

In summary, epidemiological evidence suggests that consuming a wide variety of fruits and vegetables that containing high concentrations of bioactive phytochemical compounds may work collectively and synergistically to lower the risk for developing AD. Relatively few experimental clinical trials have been published assessing the effects of plant/phytochemical consumption on AD in humans. Several experimental preclinical studies using transgenic animals and/or in vitro models have provided evidence that various aspects of AD neuropathology can be manipulated by plants and their phytochemicals. The following subsections outline recent experimental literature describing the varied potential benefits of bioactive phytochemicals on AD neuropathology.

4.2. Experimental evidence

4.2.1. Polyphenols

Many plants produce polyphenols (large assemblies of phenols, which are molecules that contain an aromatic ring bonded to a hydroxyl group). These include common phytochemicals like the phenolic acids, stilbenoids, and flavonoids.

4.2.1.1. Phenolic acids

Several phenolic acids have been shown to modulate neuropathological pathways related to AD. For example, rosmarinic acid (derived from rosemary) and nordihydroguaiaretic acid (derived from creosote) have been shown to prevent and reverse Aβ aggregation in vitro (140-142). Additionally, coffee and tea are plants with relatively high concentrations of phenolic acids that possess antioxidant and anti-inflammatory properties, such as caffeic acid and various tannins (143-146). Coffee and tea are also discussed in section 4.2.6.1. (caffeine), and tea is discussed in more detail in section 4.2.1.3.1. (flavans).

Diets containing high amounts of the spice mixture curry have been associated with improved cognitive performance in elderly individuals (134, 147). Curcumin is a phenolic acid found in the curry spice turmeric, which is a bright yellow root related to ginger. It is structurally similar to thioflavine-S and Congo red, which are histological stains used to visualize amyloid fibrils in brain tissue. Interestingly, curcumin will also bind to amyloid fibrils in brain tissue sections and can be visualized under a fluorescent microscope to observe Aβ plaques(148, 149). In addition to its Aβ binding properties in tissue sections, it has also been demonstrated to prevent and reverse Aβ aggregation in vitro (150, 151).

Experimentally, dietary curcumin has been reported to prevent oxidative stress, synaptic damage, cortical microgliosis, and learning deficits in rats after intracerebroventricular infusion of Aβ (152). It also decreased Aβ plaques and oxidative stress in APP transgenic mice (150, 151, 153) and reduced heme-Aβ peroxidase damage to muscarinic ACh receptors (35). More recent studies with both rats and mice have examined whether curcumin attenuates inflammation and mitochondrial dysfunction in models of neurological insult. The results suggested that curcumin reduced post-insult lesion sizes and inflammatory biomarkers in the brain, and improved mitochondrial function and behavioral outcomes (100, 154). Additionally, a transgenic mouse study demonstrated increased levels of DNA damage relative to control mice, and reported that dietary supplementation with curcumin significantly reduced the damage (155). Its experimental effects are not limited to rodent models. A recent drosophila (fruit fly) experiment found that curcumin reduced oxidative stress and protected against age-related neurodegeneration (156), and a study of elderly humans after 12 weeks of curcumin supplementation demonstrated improved artery endothelial function by increased vascular nitric oxide bioavailability, reduced overall oxidative stress, and improved conduit artery endothelial function (157). Curcumin also inhibits the pro-inflammatory cytokine nuclear transcription factor-κβ (NF-κβ) (158) and modulates other cell-signaling pathways (159) . Curcumin also possesses potent antimicrobial properties which may possibly have direct or indirect effects on Aβ aggregation or other neuropathological pathways to AD. An In vitro study of curcumin demonstrated that curcumin dose-dependently inhibits the formation of Aβ fibrils and destabilizes already formed Aβ fibrils. However, the mechanism by which Curcumin inhibits Aβ fibril formation and Aβ fibril destabilization remains unclear and could be due to a synergistic effect of curcumin’s anti-aging and anti-microbial properties (150, 160, 161).

The anti-amyloid and antioxidant activity of curcumin has generated great interest for the treatment of AD. However, the insolubility of curcumin in water has restricted its use. This restriction may be overcome by the synthesis of curcumin nanoparticles that maintain anti-oxidative properties, are non-cytotoxic, and can destroy amyloid aggregates, thus approaching the treatment of Alzheimer’s disease from several angles.

Pomegranates have been consumed as food and used medicinally for millennia and contain high concentrations of punicalagins, which break down in water to smaller phenolic acids such as ellagic acid, ellagitannins, and gallic acid (162-171). Several animal and human studies have shown that pomegranate juice and extracts demonstrate significant bioactive properties, including antioxidant and anti-inflammatory effects (166, 172-186). Pomegranate juice, extracts, and their bioactive constituents suppress inflammatory cell signaling, reduce expression of oxidation-sensitive genes and pro-inflammatory cytokines in response to cellular stress, reduce blood biomarkers of inflammation and oxidative stress, and modulate endothelial nitric oxide synthase expression (187-189).

Animal experiments in which rodents have been given pomegranate extracts or had pomegranate juiced added to their drinking water have demonstrated the neuroprotective effects of the pomegranate’s bioactive phytochemicals. The amount of juice consumed was similar, on a mg/kg basis, to a human dose of 1 to 2 cups of pure pomegranate juice. Initially, pomegranate’s neuroprotective propertied were demonstrated when the offspring of pomegranate-supplemented pregnant mice were protected from neonatal hypoxic-ischemic brain injury (190). These results prompted experiments with APP transgenic mice, in which 6 months of consumption reduced Aβ plaques in the hippocampus and improved maze performance (79). Later experiments suggested that the reduction in Aβ levels likely resulted from modulations in APP enzymatic processing, presumably leading to less production of Aβ and increased production of soluble APP-α (sAPPα, an endogenous neuroprotective peptide produced by α-secretase processing of APP). Another study showed that ellagic acid derived from pomegranate rinds inhibited β-secretase activity in vitro (191). More recent mouse studies examining the consumption of pomegranate peel extract showed increased brain-derived neurotrophic factor expression and reduced Aβ plaque density, AChE activity, lipid peroxidation, and pro-inflammatory cytokine expression (192). These results were similar to other APP transgenic mouse studies in which pomegranate juice supplementation improved learning and memory and reduced Aβ plaque deposition (193) and showed significant improvements in memory, learning, and locomotor function while reducing anxiety (194). Another recent mouse study showed that pomegranate supplementation protected against proton irradiation-induced anxiety (195). Finally, pomegranate supplementation has been experimentally demonstrated to improve cognitive performance in humans after heart surgery (196) and with mild cognitive impairment (197).

Overall, this growing body of experimental evidence shows that the phenolic acids found in pomegranates may directly or indirectly provide significant behavioral and neuropathological protection against age-related disorders, including AD, by multiple mechanisms that work together to prevent establishment and progression of Aβ deposition and neurodegeneration. Interestingly, in vitro experiments show that isolated phytochemical components may not provide as much benefit as the whole juice, suggesting that the wide variety of phenolic acid isoforms present in the whole fruit may provide synergistic benefits (185). One study even showed that the conjugated sucroses, fructoses, and glucoses found in pomegranates also have antioxidant properties (183). Some recent studies have shown that bacteria in the gut can metabolize the large punicalagins into smaller anti-inflammatory molecules like urolithin-A that may have higher bioavailability (166, 198-200). These findings suggest that further comparative studies of isolated phytochemical metabolites may lead to increased understanding of their true mechanisms of action and the mediating role of microbiome metabolism. Finally, numerous other studies have shown pomegranate and its bioactive constituents to be anti-carcinogenic, antibacterial, anti-apoptotic, and protective for the cardiovascular system (172, 180-186, 201-209), suggesting that consumption of pomegranates and their juice may protect against AD neuropathology and a several other age-related disease processes.

4.2.1.2. Stilbenoids

Resveratrol is a stilbenoid polyphenol found in grapes and nuts that has been shown to induce Aβ clearance and decrease Aβ levels in vivo in part via intracellular proteasome-facilitated degradation of Aβ (210). Additionally, resveratrol modulates several Aβ-related cell-signaling pathways (211-213), which may explain the epidemiological evidence for a decreased risk of developing AD among elderly individuals who drink small to moderate amounts of wine. Experimental models of traumatic brain injury have demonstrated that treatment with resveratrol immediately after traumatic brain injury reduces oxidative stress and even reduces lesion volume (214). These findings are supported by resveratrol’s neuroprotective effects in adult and neonatal rodent models of ischemic stroke (215, 216).

4.2.1.3. Flavonoids

The flavonoid class of polyphenols includes the flavans and pigment compounds like the anthocyanidins and anthoxanthins.

4.2.1.3.1. Flavans

The flavan class of polyphenols includes flavanols such as the catechins, which are found in high concentration in tea leaves. Catechins and phenolic acids (e.g., tannins) make up about 25% of the tea leaf, which also contains psychoactive compounds (e.g., caffeine; see section 4.2.6.1.). Tea has been used medicinally for centuries, likely because of these bioactive phytochemicals. Tea consumption is still very common globally, but epidemiological evidence correlating tea consumption with the risk of developing AD has been mixed. However, multiple lines of experimental evidence suggest that tea may protect against oxidative stress (217, 218) and that some of tea’s compounds may protect various AD-related pathways. For example, a transgenic mouse study demonstrated that an extract of black tea polyphenols significantly reduced memory impairment, oxidative damage, Aβ burden, and apoptosis (219).

Isolated catechins found in tea have been studied more in depth. Epigallocatechin-3-gallate (EGCG) is a well-characterized catechin found in tea that has been shown to decrease behavioral impairments, reduce Aβ production, and decrease y-secretase activity in transgenic mice (220). In another transgenic mouse study, EGCG treatment restored respiratory rates and membrane potential, reduced ROS production, and increased ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum (221). In addition to the neuroprotective effects of ECGC, a recent study of aging rats examined a tea extract rich in other catechins, but poor in ECGC. The data demonstrated improved learning and memory and reduced oxidative stress, suggesting that tea consumption is associated with multiple catechins having a synergistic neuroprotective effect above and beyond isolated tea catechins (222). Overall, the phenolic acids and flavonoids found in tea offer multi-faceted neuroprotection from AD via multiple mechanisms.

4.2.1.3.2. Anthocyanidins

Anthocyanidins are water soluble pigments with potent with antioxidant and anti-inflammatory properties found in high concentrations in fruits such as the blueberry (223-225). Rodent models of AD have shown that a blueberry enriched diet significantly reduced learning and memory impairments mediated by excitotoxicity and oxidative stress, decreased neuronal loss, and inhibited AChE activity (226-228). In a recent study, a single drink containing blueberry flavonoids was given to 8-10-year-old children 2 hours before a brief memory assay and was associated with overall improved delayed recall, but increased susceptibility to proactive interference (229).

4.2.1.3.3. Anthoxanthins

Anthoxanthins are another class of flavonoid pigment that includes compounds such as the flavones and flavonols. Luteolin is a flavone found in the leaves and rinds of many plants, including celery, broccoli and citrus fruits that acts on multiple pathways associated with the development of AD. Reported effects in transgenic mice include decreases in both Aβ deposition and tau phosphorylation (which can ultimately lead to NFTs in humans). Other studies using rat models of AD suggest that luteolin protects against Aβ-induced cognitive impairment by regulating the cholinergic system, inhibiting oxidative stress, and prevented hippocampal cell death in a chemically-induced model of AD. (230, 231). Additionally, luteolin has been shown to reduce neuroinflammation and Aβ deposition following experimental traumatic brain injury in transgenic mice (232). Finally, luteolin demonstrates significant antioxidant action, regulates phosphorylation (233, 234), inhibits mitochondrial dysfunction induced by myocardial insult, protects BBB permeability in AD rodent models, reduces apoptosis in Parkinson’s disease rodent models, alleviates obesity-induced cognitive impairment in a rodent model of type-2 diabetes mellitus, and has anti-carcinogenic properties in an animal model of lung cancer (235-239). Thus, like other polyphenols, luteolin seems to be readily available in the diet and may provide protection from age-related neuropathology from several different angles.

Flavonols such as fisetin, quercetin, myricetin, and kaempferol have also demonstrated bioactive properties of interest to aging and AD research. For example, fisetin, which is found in strawberries and other fruits and vegetables, enhanced cognitive performance and reduced inflammation in a rodent model of induced neurodegeneration (240). Fisetin’s affects appear to be in part attributable to increases in cAMP response element binding (CREB), which plays an important role in learning and memory mechanisms and has been shown to reduce Aβ plaque formation. Additionally, isolated preparations of quercetin and myricetin have been shown to reduce Aβ-related damage to muscarinic acetylcholine receptors (241, 242).

Kaempferol and quercetin are flavonols found in especially high concentrations in the leaves of the gingko biloba tree, which have been used medicinally for centuries due to their purported cognitive enhancing properties. In addition to kaempferol and quercetin, ginkgo biloba also contains terpenes such as ginkgolides and bilobalides (see section 4.2.2.1.). It has most often been studied experimentally using an extract known as EGb761, which has been standardized to 24% polyphenol / 6% terpene content, allowing relatively easy comparisons between experimental studies. Multiple clinical trials have shown that daily treatment with EGb761 for a period of 12-24 weeks can provide mild cognitive improvements in elderly and demented patients (243-245). A study of several thousand non-demented elderly adults compared the effects of EGb761 to piracetam on cognitive functioning over a 20-year period. Results indicated less cognitive decline in subjects taking EGb761 than those who reported regular use of piracetam (246). Another recent randomized, placebo-controlled trial of several hundred outpatients was conducted to demonstrate the efficacy and safety of EGb761 treatment for 24 weeks in patients with AD or vascular dementia. EGb76 treatment produced significant and clinically relevant improvements in cognition, psychopathology, functional measures, and quality of life for patients and caregivers. Importantly, no significant toxicities were observed (243). However, in another randomized, placebo-controlled trial, adults aged 70 years or older who presented with initial memory complaints were administered EGb761 daily and followed for conversion to probable AD diagnoses. In these subjects, EGb761 did not reduce the risk of progression to AD compared with controls given a placebo (247, 248). However, like many failed clinical trials of AD treatments, it is possible that the intervention was simply started too late, since neuropathology generally precedes the clinical symptoms by several years.

Several animal and in vitro studies have demonstrated that EGb761 can modulate multiple pathways related to both brain function and neuroprotection. For example, EGb761 has been shown to increase dopaminergic transmission in the rat PFC(249), increase production of brain derived neurotrophic factor in aged rats (250), improve mitochondrial respiration in vitro (251), and attenuate lipid peroxidation and superoxide free radical production in a mouse model of Parkinson’s disease (252) In addition to its potent antioxidant properties, EGb761 also acts as an AChE inhibitor, so several studies have compared its clinical effects to pharmaceutical AChE inhibitors. One study found that combined treatment with EGb761 and donepezil was superior to either compound alone and produced fewer side effects than mono-therapy with donepezil (253). Although AChE inhibitors have demonstrated mostly disappointing results in the treatment of AD, research into the efficacy of the extract persists because of its minimal side effect profile and other potential mechanisms of action (254). EGb761 has also been shown to reduce Aβ deposition, enhance CREB phosphorylation, and promote cell proliferation in the hippocampi of young and aged transgenic mice (255). In another study, transgenic mice that were given EGb761 for 20 weeks via dietary supplementation demonstrated significantly improved cognitive function, attenuated loss of synaptic proteins, inhibition of caspase-1, and less inflammation via microglia-induced secretion of TNF-α and IL-1β (256). This pattern of results suggests that the phytochemicals in EGb761 act on AD pathology via multiple synergistic mechanisms, including antioxidant, anti-inflammatory, and anti-AChE pathways (257, 258).

Concerns about the bioavailability of phytochemicals like EGb761, such as their ability to cross the BBB, have led to recent investigations on the pharmacokinetics of these compounds. A rat study found that repeated oral administration of standard EGb761 doses for 1 week led to as much as a 10x increase in the plasma concentration of its flavonols components, which were also found in the hippocampus, frontal cortex, striatum, and cerebellum (259). Thus, although gingko biloba is generally not considered a dietary plant, the available evidence suggests that readily available concentrated extracts may provide beneficial anti-aging and anti-AD effects via multiple pathways with a minimal side effect profile.

4.2.2. Terpenes

Terpenes are hydrocarbon compounds produced by plants (and some insects) that often have strong odors and an oily consistency. Terpenes of interest to aging and AD research include the ginkgolides and bilobalides (found in ginkgo biloba), huperzine A (found in Chinese club moss), and the phytocannabinoids (found in cannabis).

4.2.2.1. Ginkgolides and bilobalides

As mentioned above, gingko biloba is often studied using EGb761, an extract that has been standardized to contain 24% polyphenols and 6% terpenes (the ginkgolides and bilobalides). Studies using EGb761 are discussed in more detail in the previous section, and it should be noted that its polyphenols and terpenes seem to act together in a synergistic fashion to provide its neuroprotective effects (257, 258). However, at least one study suggests that ginkgolide J, one of its terpenoid components, provided similar protection from the detrimental effects of Aβ on long term potentiation as the whole extract (260).

4.2.2.2. Huperzine A

Huperzine A is a terpene alkaloid with AChE inhibiting properties found in the toothed clubmoss plant. It has been shown to promote neurogenesis in the rodent dentate gyrus (261) and protect mitochondria against Aβ deposition by preserving membrane integrity and improving energy metabolism (262). Both huperzine A and Huprine X, which is synthesized by combining components of huperzine A with a synthetic AChE inhibitor, improved learning and memory in a transgenic mouse model of AD (263, 264). However, recent clinical trials have yielded mixed results, and the low availability of toothed clubmoss, along with the relatively poor performance of pharmaceutical acetylcholinesterase inhibitors, has slowed progress (265).

4.2.2.3. Cannabinoids

Cannabis is a plant with long history of both medicinal and recreational use. Cannabis contains a wide variety of terpenes, collectively known as phytocannabinoids, that bind with CB1 and CB2 cannabinoid receptors. CB1 receptors are expressed mainly in the cerebral cortex and are thought to be responsible for cannabis’ well-documented psychoactive effects. CB2 receptors are expressed mainly in the periphery and are thought to play a role in a variety of inflammatory processes. These compounds, including tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), have structural similarity to endogenous cannabinoid neurotransmitters such as anandamide and 2-AG, and are antioxidant, anti-inflammatory, and neuroprotective against excitotoxicity and acute brain damage (266, 267). Additionally, phytocannabinoids have been demonstrated to enhance mitochondrial functioning (268) and stimulate neurogenesis within the embryonic and adult hippocampus (269, 270).

Aging is associated with dysregulation of cannabinoid receptor expression (271), and stimulation of cannabinoid receptors with synthetic cannabinoids has been shown to attenuate these effects (272, 273). A recent study demonstrated that THC restored cognitive performance in older mice, but, interestingly, the opposite effect was observed in younger mice (274). Several studies have suggested multiple mechanisms by which cannabinoids, including the phytocannabinoids found in cannabis, can also affect AD process. There is currently no conclusive epidemiological evidence on long-term cannabis users and a reduced incidence of AD, but multiple lines of experimental evidence suggest a possible protective effect. Although the relationship between cannabinoid receptors and AD pathogenesis remains unclear, cannabinoid receptor expression and the activity levels of enzymes that control endogenous cannabinoid concentrations change with the development of AD (272). Postmortem studies of AD and Down syndrome brains reveal consistently elevated levels of CB2 expression, whereas CB1 receptors are often reduced (275, 276) (277-279). These and other observations suggest that endogenous cannabinoids such as 2-AG mediate inflammatory and neuroprotective processes (280, 281).

A study of transgenic mice that also lacked CB1 receptors reported that despite a decrease in Aβ plaque load, significant learning and memory deficits persisted, suggesting that that CB1 receptor deficiency can worsen AD-related cognitive deficits independent of Aβ plaque load (282). Another study showed that the rate of Aβ clearance across the BBB was doubled by stimulation of the endogenous cannabinoid 2-arachidonoylglycerol (2AG) via inhibition of endogenous cannabinoid-degrading enzymes (271, 283). Furthermore, another study demonstrated that treatment with a synthetic CB2 agonist reduced Aβ-induced memory loss (284), and in vitro data shows that THC inhibits Aβ aggregation via indirect interaction with Aβ peptides (285). Finally, studies of synthetic cannabinoids have shown them to ameliorate cognitive impairment and neurodegeneration in multiple models of Aβ-induced neurotoxicity and neuroinflammation independent of antioxidant and/or psychoactive properties (286-288). Thus, cannabinoids, including those found in cannabis, seem to act on age-related and AD-specific neuropathological processes through multiple pathways, suggesting a potential role for exogenous (e.g., phyto- or synthetic) cannabinoids in the prevention and/or treatment of AD.

4.2.3. Organosulphurs

Garlic contains many aromatic sulfur-containing phytochemicals, including s-allyl cysteine (SAC) and di-allyl disulfide, collectively known as organosulfurs. Adding an aged garlic extract, SAC, or di-allyl-disulfide to the diets of transgenic mice has been shown to ameliorate cognitive deficits, reduce Aβ plaque formation, reduce abnormal tau build-up, and reduce oxidative damage (289-293). SAC has been shown to inhibit and reverse Aβ aggregation in vitro and in transgenic mice by binding directly to the Aβ peptide (294). Another in vitro study examining the neuroprotective potential of SAC found reduced apoptosis that was not attributable to antioxidant activity, but rather to suppression of calpain proteins (295, 296). The isolated components of SAC also appear to have AD-related neuroprotective properties, and may produce a synergistic effect in combination with di-allyl-disulfide. Together, these findings suggest that garlic and its organosulfur compounds may act on several pathways to reduce Aβ plaque formation and other AD neuropathology.

4.2.4. Fatty acids

Omega-3 fatty acids, such as α-linolenic acid, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are found mainly in flax, nuts, algae, and certain fish. DHA and EPA make up about 15% of the human brain’s total fatty acids and 30-40% of its gray matter. Consuming omega-3 fatty acids can reduce inflammation, improve learning and memory, increase gray matter volume, and alter gut microbiota composition. DHA has been shown to protect against Aβ-induced neurotoxicity in transgenic mice and has demonstrated anti-inflammatory and anticancer properties (297-299). In vitro studies have shown that DHA and EPA can reduce Aβ aggregation, increase production of neurotrophic substances, and decrease production of pro-inflammatory cytokines (300). Additionally, omega-3 derivatives can promote α-secretase processing of APP, which prevents the production of Aβ and leads instead to the production of the neuroprotective peptide sAPPα (299). A recent study of AD patients found that 24 weeks of omega-3 supplementation produced increased levels of EPA and DHA in plasma and cerebrospinal fluid (CSF) that were inversely correlated with CSF levels of phosphorylated tau (301). However, another recent study demonstrated that Aβ pathology may limit the ability of DHA to readily cross the BBB, which may explain why several clinical trials have yielded inconclusive or negative results, despite the high bioavailability of DHA (302, 303).

4.2.5. Phytovitamins

Epidemiological evidence mentioned in section 4.1. suggests a protective effect of dietary vitamins against the risk of developing AD, and experimental evidence with humans and rodents tends to support this idea. Tocopherols (isoforms of vitamin E) and folic acid (an isoform of vitamin B9) are found in several commonly consumed plants. A recent clinical trial of vitamin E supplementation in AD patients taking AChE inhibitors reported a 19% per year delay in clinical progression (304), but recent clinical trials of vitamin E in isolation have yielded less promising results, suggesting that vitamin E may be better suited as a complementary therapy for AD (122). However, in a study of aged rats, vitamin E-supplementation improved age-related cognitive deficits (305), and several transgenic mouse studies have demonstrated beneficial AD-related effects of supplementing with vitamin E. For example, dietary administration of vitamin E to transgenic mice reduced Aβ deposition (306) along with its associated oxidative stress and neuritic dystrophy (307), and it ameliorated behavioral impairments, oxidative stress, and injury-accelerated Aβ formation resulting from repetitive traumatic brain injury (308). Therefore, the data suggest that dietary tocopherols may protect the brain from Aβ deposition and its associated functional decline.

Other studies have focused on B vitamins, because dietary deficiencies have been associated with cognitive decline and an increase in AD-related neuropathology. For example, a study of elderly individuals with a vitamin B deficiency found that reversing the deficiency with folic acid (an isoform of vitamin B9 found in many fruits and vegetables) improved cognitive function after 14 weeks (309). A transgenic mouse study looked at the effects of dietary folic acid deficiency on neuropathology in transgenic mice and reported significant neurodegeneration within the hippocampus, although Aβ levels were not affected (310). An in vitro study of folic acid deprivation demonstrated increased expression of the genes involved in encoding the γ- and β-secretases along with increased levels of Aβ (311). In a study of high dose B vitamin supplements given to healthy adult participants over 4-weeks, increased task-related functional brain activity was reported (312). However, a similar high dose combination of vitamins B6 and B12 was ineffective at slowing cognitive decline in individuals with mild to moderate AD, suggesting that vitamin B may be more effective as a preventive measure for AD than as an acute intervention for AD related cognitive decline (313). Other trials of folic acid supplementation in humans have shown that its long-term consumption is associated with decreased plasma levels of Aβ and increased grey matter volume in the brain (314, 315). These studies, along with data showing the neuroprotective effects of folic acid on the developing nervous system and the anti-oxidant properties of dietary tocopherols, suggest that consuming phytovitamins may offer neuroprotection from oxidative stress that contributes to increased Aβ deposition and AD progression.

4.2.6. Psychoactive alkaloids

4.2.6.1. Caffeine

Although tea and coffee contain high levels of beneficial polyphenol compounds, the psychoactive alkaloid caffeine explains their global popularity. Caffeine functions as an insecticide in plants and as a psychostimulant in animals. Because its stimulant effects (resulting from its competitive inhibition of adenosine receptors in the brain) are not associated with the euphoria and addictive properties characterized by other psychostimulants (e.g., cocaine and amphetamines), caffeine has been used centuries throughout the globe as a general cognitive enhancer. Recent studies with animal models of AD have shown that caffeine consumption is associated with protection against oxidative stress, improved mitochondrial functioning and BBB permeability, increased expression of brain derived neurotrophic factor, and reduced Aβ deposition and associated cognitive deficits (316-320). One study compared pure caffeine to “crude” caffeine, which is derived from coffee during the decaffeination process and likely contains other compounds (e.g., phenolic acids). Both supplements had beneficial effects in a transgenic mouse model of AD, including neuroprotection from Aβ-induced neuronal death via suppressed caspase-3 activity. However, crude caffeine was more effective in reducing learning and memory deficits, and only crude caffeine reduced hippocampal Aβ deposition, suggesting that “phyto”-caffeine may offer protection from AD-related processes above and beyond that produced by pure caffeine (321). Interestingly, “caffeinol” (a combination of caffeine and ethanol) has been shown to demonstrate potent synergistic neuroprotection in rodent models of stroke (322-324). Caffeine’s mild stimulant effects may improve cognition, and it appears to offer multiple synergistic pathways of neuroprotection from AD pathology, including inhibition of Aβ aggregation and protection from neurologic insult.

4.2.6.2. Nicotine

Nicotine is another alkaloid that protects the tobacco plant from insect predators and produces psychostimulant effects in animals, primarily due to its agonist action at nicotinic acetylcholine receptors. Like caffeine, nicotine has a long history of human use at least partially due to its stimulant and cognitive enhancement properties. Although some previous studies have demonstrated in both humans and animals that nicotine may have potential neuroprotective effects on AD pathology, further research has demonstrated that smokers are at a significantly higher risk of developing AD via multiple pathways (325-327). Chronic nicotine administration in transgenic mouse models of AD has been shown to increase levels of brain-derived neurotrophic factor and prevent long-term memory impairment induced by Aβ deposition (328, 329). Possible mechanisms include activity at the nicotinic acetylcholine receptors, which results in decreased oxidative damage, Aβ deposition, and apoptosis. In addition to the potential cognitive enhancement, antioxidant, and anti-Aβ actions attributed to nicotine, its psychoactive metabolite, nornicotine, has been show to inhibit Aβ aggregation by forming permanent covalent bonds with Aβ peptides (330). These finding suggest that pharmaceutical treatment with nicotine may provide positive benefits in the treatment and/or prevention of AD.

5. Summary

The development of AD-related neuropathology and its associated behavioral deficits is related to the gradual accumulation of Aβ plaques and NFTs in the cortex over the lifespan. This causes increased oxidative stress and inflammation in the brain, leading to further Aβ deposition, neuronal degradation, and other downstream effects. A variety of acute or low-grade chronic neurological insults can accelerate this process, and current pharmacological treatment options appear to be only minimally beneficial.

In the absence of effective pharmaceutical therapies for AD, focusing on lifestyle factors associated with reducing risk of developing AD appears to be the most effective preventive measure. The difficulty of demonstrating consistent beneficial effects of phytochemicals in humans is not surprising, given the similar failures of pharmacological interventions. Nevertheless, several lines of research demonstrate that long-term consumption of various phytochemicals may attenuate multiple neuropathological processes associated with the development of AD. The results of experimental data from animal studies and clinical trials, along with a growing body of epidemiological studies, lend credibility to the idea that bioactive phytochemicals can have beneficial effects via multiple mechanisms related to general brain aging, including regulation of the intestinal/gut microbiome and BBB permeability, modulation of neurotransmitter degradation and binding, anti-inflammatory and antioxidant effects, reduced susceptibility to excitotoxicity and apoptosis, stimulation of neurogenesis and long-term potentiation, and maintenance of proper mitochondrial function and other cellular processes related to learning and memory (331, 332). Additionally, bioactive phytochemicals have demonstrated beneficial effects on multiple AD-specific processes, including inhibition of Aβ production by modulating enzymatic processes and reducing Aβ deposition in the brain by decreasing aggregation and increasing clearance.

Given that AD is progressive, insidious, and ultimately fatal disease effecting a significant portion of older individuals, delaying the onset of AD by even a slight margin would significantly impact its incidence. Mounting epidemiological and experimental evidence suggests that a lifetime of consuming an abundance of neuroprotective phytochemicals may provide significant protection from environmental and age-related insults that accelerate the progression of AD neuropathology (76, 194, 333). Furthermore, diets containing a wide variety of bioactive phytochemicals from multiple plant sources may provide synergistic benefits over supplementing with isolated compounds (334, 335). Finally, chronic adherence to diets rich in diverse sources of bioactive dietary polyphenols may protect against neurodegenerative disorders such as AD, but may also confer additional health and age-related benefits.

Abbreviations: Aβ: Amyloid Beta; AChE: acetylcholinesterase; AD: Alzheimer’s Disease; APP: Amyloid Precursor Protein; BBB: Blood Brain Barrier; CREB: cAMP response element binding protein; EGCG: epigallocatechin-3-gallate; NFT: neurofibrillary tangle; sAPPα: soluble APP-α; SAC: s-allyl cysteine

References

    1. L. Rossi, S. Mazzitelli, M. Arciello, C. R. Capo and G. Rotilio: Benefits from Dietary Polyphenols for Brain Aging and Alzheimer’s Disease. Neurochem Res, 33, 2390-2400 (2008)
    DOI: 10.1007/s11064-008-9696-7

    2. M. Singh, M. Arseneault, T. Sanderson, V. Murthy and C. Ramassamy: Challenges for Research on Polyphenols from Foods in Alzheimer’s Disease: Bioavailability, Metabolism, and Cellular and Molecular Mechanisms. J Agric Food Chem, 56, 4855-4873 (2008)
    DOI: 10.1021/jf0735073

    3. Alzheimer’s. Association: 2014 Alzheimer’s Disease Facts and Figures. Alzheimers Dement, 10, 1-80 (2014)
    DOI: 10.1016/j.jalz.2014.02.001

    4. S. J. Soscia, J. E. Kirby, K. J. Washicosky, S. M. Tucker, M. Ingelsson, B. Hyman, M. A. Burton, L. E. Goldstein, S. Duong, R. E. Tanzi and R. D. Moir: The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One, 5, e9505 (2010)
    DOI: 10.1371/journal.pone.0009505

    5. R. Alonso, D. Pisa, A. I. Marina, E. Morato, A. Rábano and L. Carrasco: Fungal Infection in Patients with Alzheimer’s Disease. J Alzheimers Dis, 41, 301-311 (2014)

    6. L. Devi and H. K. Anandatheerthavarada: Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases. Biochim Biophys Acta, 1802, 11-19 (2010)
    DOI: 10.1016/j.bbadis.2009.07.007

    7. P. I. Moreira, C. Carvalho, X. Zhu, M. A. Smith and G. Perry: Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta, 1802, 2-10 (2010)
    DOI: 10.1016/j.bbadis.2009.10.006

    8. Y. Yao, C. Chinnici, H. Tang, J. Q. Trojanowski, V. M. Lee and D. Praticò: Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis. J Neuroinflammation, 1, 21 (2004)
    DOI: 10.1186/1742-2094-1-21

    9. J. M. Rubio-Perez and J. M. Morillas-Ruiz: A Review: Inflammatory Process in Alzheimer’s Disease, Role of Cytokines. Scientific World J, 2012, 1-15 (2012)
    DOI: 10.1100/2012/756357

    10. Q. S. Xue, D. L. Sparks and W. J. Streit: Microglial activation in the hippocampus of hypercholesterolemic rabbits occurs independent of increased amyloid production. J Neuroinflammation, 4, 20 (2007)
    DOI: 10.1186/1742-2094-4-20

    11. D. Terwel, K. R. Steffensen, P. B. Verghese, M. P. Kummer, J. A. Gustafsson, D. M. Holtzman and M. T. Heneka: Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci, 31(19), 7049-59 (2011)
    DOI: 10.1523/JNEUROSCI.6546-10.2011

    12. J. D. Cherry, J. A. Olschowka and M. K. O’Banion: Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation, 11, 98 (2014)
    DOI: 10.1186/1742-2094-11-98

    13. B. V. Zlokovic: The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 57(2), 178-201 (2008)
    DOI: 10.1016/j.neuron.2008.01.003

    14. T. A. Bayer and O. Wirths: Intracellular accumulation of amyloid-Beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease. Front Aging Neurosci, 2, 8 (2010)
    DOI: 10.3389/fnagi.2010.00008

    15. N. Z. Borgesius, M. C. de Waard, I. van der Pluijm, A. Omrani, G. C. M. Zondag, G. T. J. van der Horst, D. W. Melton, J. H. J. Hoeijmakers, D. Jaarsma and Y. Elgersma: Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci, 31, 12543-53 (2011)
    DOI: 10.1523/JNEUROSCI.1589-11.2011

    16. M. L. Block and J. S. Hong: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol, 76(2), 77-98 (2005)
    DOI: 10.1016/j.pneurobio.2005.06.004

    17. D. E. Bredesen: Neurodegeneration in Alzheimer’s disease: caspases and synaptic element interdependence. Mol Neurodegener, 4(1), 27 (2009)
    DOI: 10.1186/1750-1326-4-27

    18. K. Schindowski, S. Leutner, S. Kressmann, A. Eckert and W. E. Müller: Age-related increase of oxidative stress-induced apoptosis in mice prevention by Ginkgo biloba extract (EGb761). J Neural Transm (Vienna), 108, 969-978 (2001)
    DOI: 10.1007/s007020170016

    19. A. Houlden, M. Goldrick, D. Brough, E. S. Vizi, N. Lenart, B. Martinecz, I. S. Roberts and A. Denes: Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav Immun, 57, 10-20 (2016)
    DOI: 10.1016/j.bbi.2016.04.003

    20. O. Wirths, G. Multhaup and T. A. Bayer: A modified beta-amyloid hypothesis: intraneuronal accumulation of the beta-amyloid peptide - the first step of a fatal cascade. J Neurochem, 91, 513-520 (2004)
    DOI: 10.1111/j.1471-4159.2004.02737.x

    21. J. Dong, C. S. Atwood, V. E. Anderson, S. L. Siedlak, M. A. Smith, G. Perry and P. R. Carey: Metal binding and oxidation of amyloid-β within isolated senile plaque cores: Raman microscopic evidence. Biochemistry, 42, 2768-2773 (2003)
    DOI: 10.1021/bi0272151

    22. A. E. Roher, K. C. Palmer, E. C. Yurewicz, M. J. Ball and B. D. Greenberg: Morphological and Biochemical Analyses of Amyloid Plaque Core Proteins Purified from Alzheimer Disease Brain Tissue. J Neurochem, 61, 1916-1926 (1993)
    DOI: 10.1111/j.1471-4159.1993.tb09834.x

    23. R. F. Rosen, Y. Tomidokoro, A. S. Farberg, J. Dooyema, B. Ciliax, T. M. Preuss, T. A. Neubert, J. A. Ghiso, H. LeVine and L. C. Walker: Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging, 44, 185-196 (2016)
    DOI: 10.1016/j.neurobiolaging.2016.04.019

    24. M. Mohsenzadegan and A. Mirshafiey: The immunopathogenic role of reactive oxygen species in Alzheimer disease. Iran J Allergy Asthma Immunol, 11, 203-216 (2012)

    25. V. L. Villemagne, K. E. Pike, G. Chételat, K. A. Ellis, R. S. Mulligan, P. Bourgeat, U. Ackermann, G. Jones, C. Szoeke, O. Salvado, R. Martins, G. O’Keefe, C. A. Mathis, W. E. Klunk, D. Ames, C. L. Masters and C. C. Rowe: Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol, 69, 181-192 (2011)
    DOI: 10.1002/ana.22248

    26. J. J. Palop and L. Mucke: Amyloid-(beta)-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci, 13(7), 812-818 (2010)
    DOI: 10.1038/nn.2583

    27. D. J. Selkoe: Alzheimer’s disease is a synaptic failure. Science, 298, 789-791 (2002)
    DOI: 10.1126/science.1074069

    28. J. Reifert, D. Hartung-Cranston and S. C. Feinstein: Amyloid Beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length Tau phosphorylation. J Biol Chem, 286, 20797-20811 (2011)
    DOI: 10.1074/jbc.M111.234674

    29. O. A. Shipton, J. R. Leitz, J. Dworzak, C. E. J. Acton, E. M. Tunbridge, F. Denk, H. N. Dawson, M. P. Vitek, R. Wade-Martins, O. Paulsen and M. Vargas-Caballero: Tau Protein Is Required for Amyloid β-Induced Impairment of Hippocampal Long-Term Potentiation. J Neurosci, 31, 1688 -1692 (2011)
    DOI: 10.1523/JNEUROSCI.2610-10.2011

    30. R. Kimura, D. MacTavish, J. Yang, D. Westaway and J. H. Jhamandas: Beta amyloid-induced depression of hippocampal long-term potentiation is mediated through the amylin receptor. J Neurosci, 32, 17401-6 (2012)
    DOI: 10.1523/JNEUROSCI.3028-12.2012

    31. D. M. Walsh, I. Klyubin, J. V. Fadeeva, W. K. Cullen, R. Anwyl, M. S. Wolfe, M. J. Rowan and D. J. Selkoe: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535-539 (2002)
    DOI: 10.1038/416535a

    32. M. Matos, E. Augusto, C. R. Oliveira and P. Agostinho: Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: Involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience, 156, 898-910 (2008)
    DOI: 10.1016/j.neuroscience.2008.08.022

    33. M. Nakayama, M. Aihara, Y.N. Chen, M. Araie, K. Tomita-Yokotani and T. Iwashina: Neuroprotective effects of flavonoids on hypoxia-, glutamate-, and oxidative stress-induced retinal ganglion cell death. Mol Vis, 17, 1784 (2011)

    34. J. R. Fawcett, E. Z. Bordayo, K. Jackson, H. Liu, J. Peterson, A. Svitak and W. H. Frey II: Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer’s brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants. Brain Res, 950, 10-20 (2002)
    DOI: 10.1016/S0006-8993(02)02981-5

    35. H. Atamna, W. H. Frey and N. Ko: Human and rodent amyloid-Beta peptides differentially bind heme: Relevance to the human susceptibility to Alzheimer’s disease. Arch Biochem Biophys, 487, 59-65 (2009)
    DOI: 10.1016/j.abb.2009.05.003

    36. T. Hamaguchi, K. Ono and M. Yamada: Anti-amyloidogenic therapies: Strategies for prevention and treatment of Alzheimer’s disease. Cell Mol Life Sci, 63, 1538-1552 (2006)
    DOI: 10.1007/s00018-005-5599-9

    37. T. Kiko, K. Nakagawa, A. Satoh, T. Tsuduki, K. Furukawa, H. Arai and T. Miyazawa: Amyloid β Levels in Human Red Blood Cells. PLoS One, 7, 1-6 (2012)
    DOI: 10.1371/journal.pone.0049620

    38. J. M. Peake, K. Suzuki and J. S. Coombes: The influence of antioxidant supplementation on markers of inflammation and the relationship to oxidative stress after exercise. J Nutr Biochem, 18, 357-371 (2007)
    DOI: 10.1016/j.jnutbio.2006.10.005

    39. P. Giannakopoulos, F. R. Herrmann, T. Bussière, C. Bouras, E. Kövari, D. P. Perl, J. H. Morrison, G. Gold and P. R. Hof: Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology, 60, 1495-500 (2003)
    DOI: 10.1212/01.WNL.0000063311.58879.01

    40. C. Schmitz, B. P. Rutten, A. Pielen, S. Schafer, O. Wirths, G. Tremp, C. Czech, V. Blanchard, G. Multhaup, P. Rezaie, H. Korr, H. W. Steinbusch, L. Pradier and T. A. Bayer: Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol, 164, 1495-1502 (2004)
    DOI: 10.1016/S0002-9440(10)63235-X

    41. D. Tosun, N. Schuff, C. A. Mathis, W. Jagust, M. W. Weiner and A. s. D. N. Initiative: Spatial patterns of brain amyloid-beta burden and atrophy rate associations in mild cognitive impairment. Brain, 134, 1077-88 (2011)
    DOI: 10.1093/brain/awr044

    42. V. L. Villemagne, S. Burnham, P. Bourgeat, B. Brown, K. A. Ellis, O. Salvado, C. Szoeke, S. L. Macaulay, R. Martins, P. Maruff, D. Ames, C. C. Rowe and C. L. Masters: Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol, 12, 357-367 (2013)
    DOI: 10.1016/S1474-4422(13)70044-9

    43. E. Head, B. Y. Azizeh, I. T. Lott, a. J. Tenner, C. W. Cotman and D. H. Cribbs: Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome. Neurobiol Dis, 8, 252-65 (2001)
    DOI: 10.1006/nbdi.2000.0380

    44. W. J. Netzer, C. Powell, Y. Nong, J. Blundell, L. Wong, K. Duff, M. Flajolet and P. Greengard: Lowering β-amyloid levels rescues learning and memory in a down syndrome mouse model. PLoS One, 5 (2010)
    DOI: 10.1371/journal.pone.0010943

    45. N. Schupf, B. Patel, D. Pang, W. B. Zigman, W. Silverman, P. D. Mehta and R. Mayeux: Elevated plasma beta-amyloid peptide Abeta(42) levels, incident dementia, and mortality in Down syndrome. Arch Neurol, 64, 1007-13 (2007)
    DOI: 10.1001/archneur.64.7.1007

    46. T. D. Bird: Genetic aspects of Alzheimer disease. Genet Med, 10, 231-239 (2008)
    DOI: 10.1097/GIM.0b013e31816b64dc

    47. R. Cacace, K. Sleegers and C. Van Broeckhoven: Molecular genetics of early-onset alzheimer disease revisited. Alzheimers Dement, 12, 733-748 (2016)
    DOI: 10.1016/j.jalz.2016.01.012

    48. J. Krüger, V. Moilanen, K. Majamaa and A. M. Remes: Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset alzheimer Disease and Frontotemporal Lobar Degeneration. Alzheimer Dis Assoc Disord, 26, 272-276 (2012)
    DOI: 10.1097/WAD.0b013e318231e6c7

    49. R. M. Cohen, K. Rezai-Zadeh, T. M. Weitz, A. Rentsendorj, D. Gate, I. Spivak, Y. Bholat, V. Vasilevko, C. G. Glabe, J. J. Breunig, P. Rakic, H. Davtyan, M. G. Agadjanyan, V. Kepe, J. R. Barrio, S. Bannykh, C. A. Szekely, R. N. Pechnick and T. Town: A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci, 33, 6245-56 (2013)
    DOI: 10.1523/JNEUROSCI.3672-12.2013

    50. K. Hochgräfe, A. Sydow and E. M. Mandelkow: Regulatable transgenic mouse models of Alzheimer disease: Onset, reversibility and spreading of Tau pathology. FEBS J, 280, 4371–4381 (2013)
    DOI: 10.1111/febs.12250

    51. M. Kitazawa, R. Medeiros and F. M. LaFerla: Transgenic Mouse Models of Alzheimer Disease: Developing a Better Model as a Tool for Therapeutic Interventions. Curr Pharm Des, 18, 1131-1147 (2012)
    DOI: 10.2174/138161212799315786

    52. D. A. Morrissette, A. Parachikova, K. N. Green and F. M. LaFerla: Relevance of transgenic mouse models to human Alzheimer disease. J Biol Chem, 284, 6033-7 (2009)
    DOI: 10.1074/jbc.R800030200

    53. R. E. Hartman, J. M. Lee, G. J. Zipfel and D. F. Wozniak: Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats. Brain Res, 1043(1-2), 48-56 (2005)
    DOI: 10.1016/j.brainres.2005.02.030

    54. M. Meyer-Luehmann, T. L. Spires-Jones, C. Prada, M. Garcia-Alloza, A. de Calignon, A. Rozkalne, J. Koenigsknecht-Talboo, D. M. Holtzman, B. J. Bacskai and B. T. Hyman: Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease. Nature, 451, 720-724 (2008)
    DOI: 10.1038/nature06616

    55. P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman and J.-M. Lee: Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice. J Neurosci, 29(34), 10706-10714 (2009)
    DOI: 10.1523/JNEUROSCI.2637-09.2009

    56. P. M. Abdul-Muneer, N. Chandra and J. Haorah: Interactions of Oxidative Stress and Neurovascular Inflammation in the Pathogenesis of Traumatic Brain Injury. Mol Neurobiol, 51(3), 966-979 (2015)
    DOI: 10.1007/s12035-014-8752-3

    57. Q.-G. Zhang, M. D. Laird, D. Han, K. Nguyen, E. Scott, Y. Dong, K. M. Dhandapani and D. W. Brann: Critical Role of NADPH Oxidase in Neuronal Oxidative Damage and Microglia Activation following Traumatic Brain Injury. PLoS One, 7, e34504 (2012)
    DOI: 10.1371/journal.pone.0034504

    58. C. Beer, D. Blacker, G. J. Hankey and I. B. Puddey: Association of clinical and aetiologic subtype of acute ischaemic stroke with inflammation, oxidative stress and vascular function: A cross-sectional observational study. Med Sci Monit, 17, CR467-R473 (2011)
    DOI: 10.12659/MSM.881931

    59. Á. Chamorro, U. Dirnagl, X. Urra and A. M. Planas: Neuroprotection in acute stroke: Targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol, 15(8), 869-881 (2016)
    DOI: 10.1016/S1474-4422(16)00114-9

    60. H. Pradeep, J. B. Diya, S. Shashikumar and G. K. Rajanikant: Oxidative stress - Assassin behind the ischemic stroke. Folia Neuropathol, 50, 219-230 (2012)
    DOI: 10.5114/fn.2012.30522

    61. R. Iturriaga, E. a. Moya and R. Del Rio: Inflammation and oxidative stress during intermittent hypoxia: the impact on chemoreception. Exp Physiol, 100, 149-55 (2015)
    DOI: 10.1113/expphysiol.2014.079525

    62. S. Jelic and T. H. Le JemTel: Inflammation, Oxidative Stress, and the Vascular Endothelium in Obstructive Sleep Apnea. Trends Cardiovasc Med, 18(7), 253-260 (2008)
    DOI: 10.1016/j.tcm.2008.11.008

    63. G. Candore, M. Bulati, C. Caruso, L. Castiglia, G. Colonna-Romano, D. Di Bona, G. Duro, D. Lio, D. Matranga, M. Pellicano, C. Rizzo, G. Scapagnini and S. Vasto: Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res, 13, 301-313 (2010)
    DOI: 10.1089/rej.2009.0993

    64. J. C. Fernández-García, F. Cardona and F. J. Tinahones: Inflammation, oxidative stress and metabolic syndrome: dietary modulation. Curr Vasc Pharmacol, 11, 906-19 (2013)
    DOI: 10.2174/15701611113116660175

    65. P. J. Pistell, C. D. Morrison, S. Gupta, A. G. Knight, J. N. Keller, D. K. Ingram and A. J. Bruce-Keller: Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol, 219, 25-32 (2010)
    DOI: 10.1016/j.jneuroim.2009.11.010

    66. A. M. Stranahan, R. G. Cutler, C. Button, R. Telljohann and M. P. Mattson: Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress. J Neurochem, 118, 611-615 (2011)
    DOI: 10.1111/j.1471-4159.2011.07351.x

    67. J. M. Castellano, J. Kim, F. R. Stewart, H. Jiang, R. B. DeMattos, B. W. Patterson, A. M. Fagan, J. C. Morris, K. G. Mawuenyega, C. Cruchaga, A. M. Goate, K. R. Bales, S. M. Paul, R. J. Bateman and D. M. Holtzman: Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med, 3, 89ra57 (2011)
    DOI: 10.1126/scitranslmed.3002156

    68. L. Jofre-Monseny, A.-M. Minihane and G. Rimbach: Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res, 52, 131-45 (2008)
    DOI: 10.1002/mnfr.200700322

    69. A. Bernardo, F. E. Harrison, M. McCord, J. Zhao, A. Bruchey, S. S. Davies, L. Jackson Roberts, P. M. Mathews, Y. Matsuoka, T. Ariga, R. K. Yu, R. Thompson and M. P. McDonald: Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. Neurobiol Aging, 30, 1777-1791 (2009)
    DOI: 10.1016/j.neurobiolaging.2007.12.022

    70. R. B. Demattos, J. Lu, Y. Tang, M. M. Racke, C. A. Delong, J. A. Tzaferis, J. T. Hole, B. M. Forster, P. C. McDonnell, F. Liu, R. D. Kinley, W. H. Jordan and M. L. Hutton: A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron, 76, 908-920 (2012)
    DOI: 10.1016/j.neuron.2012.10.029

    71. J. Joseph, G. Cole, E. Head and D. Ingram: Nutrition, brain aging, and neurodegeneration. J Neurosci, 29, 12795-12801 (2009) doi:10.1.523/JNEUROSCI.3520-09.2.009
    DOI: 10.1523/JNEUROSCI.3520-09.2009

    72. E. B. Lee, L. Z. Leng, B. Zhang, L. Kwong, J. Q. Trojanowski, T. Abel and V. M.-Y. Lee: Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem, 281, 4292-9 (2006)
    DOI: 10.1074/jbc.M511018200

    73. P. Mark: The impact of dietary energy intake on cognitive aging. Front Aging Neurosci 2, 1-12 (2010)
    DOI: 10.3389/neuro.24.005.2010

    74. A. R. Patten, D. J. Moller, J. Graham, J. Gil-Mohapel and B. R. Christie: Liquid diets reduce cell proliferation but not neurogenesis in the adult rat hippocampus. Neuroscience, 254, 173-84 (2013)
    DOI: 10.1016/j.neuroscience.2013.09.024

    75. V. Pop, E. Head, M.-A. Hill, D. Gillen, N. C. Berchtold, B. A. Muggenburg, N. W. Milgram, M. P. Murphy and C. W. Cotman: Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. J Neurosci, 30, 9831-9 (2010)
    DOI: 10.1523/JNEUROSCI.6194-09.2010

    76. M. Steele, G. Stuchbury and G. Munch: The molecular basis of the prevention of Alzheimer’s disease through healthy nutrition. Exp Gerontol, 42(1-2), 28-36 (2007)
    DOI: 10.1016/j.exger.2006.06.002

    77. A. Wang, P. Das, R. C. Switzer, 3rd, T. E. Golde and J. L. Jankowsky: Robust amyloid clearance in a mouse model of Alzheimer’s disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci, 31(11), 4124-36 (2011)
    DOI: 10.1523/JNEUROSCI.5077-10.2011

    78. J. Wang, L. Ho, W. Qin, A. B. Rocher, I. Seror, N. Humala, K. Maniar, G. Dolios, R. Wang, P. R. Hof and G. M. Pasinetti: Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J, 19, 659-661 (2005)
    DOI: 10.1096/fj.04-3182fje

    79. R. E. Hartman, A. Shah, A. M. Fagan, K. E. Schwetye, M. Parsadanian, R. N. Schulman, M. B. Finn and D. M. Holtzman: Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol Dis, 24, 506-15 (2006)
    DOI: 10.1016/j.nbd.2006.08.006

    80. L. A. Kotilinek, M. A. Westerman, Q. Wang, K. Panizzon, G. P. Lim, A. Simonyi, S. Lesne, A. Falinska, L. H. Younkin, S. G. Younkin, M. Rowan, J. Cleary, R. A. Wallis, G. Y. Sun, G. Cole, S. Frautschy, R. Anwyl and K. H. Ashe: Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain, 131, 651-64 (2008)
    DOI: 10.1093/brain/awn008

    81. B. Ongali, N. Nicolakakis, X.-K. Tong, T. Aboulkassim, P. Papadopoulos, P. Rosa-Neto, C. Lecrux, H. Imboden and E. Hamel: Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis, 68, 126-136 (2014)
    DOI: 10.1016/j.nbd.2014.04.018

    82. X.-K. Tong, C. Lecrux and E. Hamel: Age-Dependent Rescue by Simvastatin of Alzheimer’s Disease Cerebrovascular and Memory Deficits. J Neurosci, 32, 4705-4715 (2012)
    DOI: 10.1523/JNEUROSCI.0169-12.2012

    83. R. A. Armstrong: A critical analysis of the ‘amyloid cascade hypothesis’. Folia Neuropathol, 3, 211-225 (2014)
    DOI: 10.5114/fn.2014.45562

    84. S. H. Barage and K. D. Sonawane: Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides, 52, 1-18 (2015)
    DOI: 10.1016/j.npep.2015.06.008

    85. E. S. Musiek and D. M. Holtzman: Three dimensions of the amyloid hypothesis: time, space and ’wingmen’. Nat Neurosci, 18, 800-806 (2015)
    DOI: 10.1038/nn.4018

    86. S. W. Pimplikar: Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol, 41(6), 1261-1268, (2009)
    DOI: 10.1016/j.biocel.2008.12.015

    87. D. M. Wilcock, A. Rojiani, A. Rosenthal, S. Subbarao, M. J. Freeman, M. N. Gordon and D. Morgan: Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation, 1(1), 24 (2004)
    DOI: 10.1186/1742-2094-1-24

    88. M. Buttini, E. Masliah, R. Barbour, H. Grajeda, R. Motter, K. Johnson-Wood, K. Khan, P. Seubert, S. Freedman and D. Schenk: β-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci, 25(40), 9096-9101 (2005)
    DOI: 10.1523/JNEUROSCI.1697-05.2005

    89. R. E. Hartman, Y. Izumi, K. R. Bales, S. M. Paul, D. F. Wozniak and D. M. Holtzman: Treatment with an Amyloid-β Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer’s Disease. The J Neurosci, 25(26), 6213-6220 (2005)
    DOI: 10.1523/JNEUROSCI.0664-05.2005

    90. S. Gilman, M. Koller, R. Black, L. Jenkins, S. Griffith, N. Fox, L. Eisner, L. Kirby, M. B. Rovira and F. Forette: Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64(9), 1553-1562 (2005)
    DOI: 10.1212/01.WNL.0000159740.16984.3C

    91. C. A. Lemere, M. Maier, L. Jiang, Y. Peng and T. J. Seabrook: Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: lessons from mice, monkeys, and humans. Rejuvenation Res, 9(1), 77-84 (2006)
    DOI: 10.1089/rej.2006.9.77

    92. E. R. Siemers, S. Friedrich, R. A. Dean, C. R. Gonzales, M. R. Farlow, S. M. Paul and R. B. DeMattos: Safety and changes in plasma and cerebrospinal fluid amyloid β after a single administration of an amyloid β monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol, 33(2), 67-73 (2010)
    DOI: 10.1097/WNF.0b013e3181cb577a

    93. F. Mangialasche, A. Solomon, B. Winblad, P. Mecocci and M. Kivipelto: Alzheimer’s disease: clinical trials and drug development. Lancet Neurol, 9(7), 702-716 (2010)
    DOI: 10.1016/S1474-4422(10)70119-8

    94. B. Winblad, N. Andreasen, L. Minthon, A. Floesser, G. Imbert, T. Dumortier, R. P. Maguire, K. Blennow, J. Lundmark and M. Staufenbiel: Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol, 11(7), 597-604 (2012)
    DOI: 10.1016/S1474-4422(12)70140-0

    95. D. Schenk, M. Hagen and P. Seubert: Current progress in beta-amyloid immunotherapy. Curr Opin Immunol, 16(5), 599-606 (2004)
    DOI: 10.1016/j.coi.2004.07.012

    96. B. Imtiaz, A. M. Tolppanen, M. Kivipelto and H. Soininen: Future directions in Alzheimer’s disease from risk factors to prevention. Biochem Pharmacol, 88(4), 661-70 (2014)
    DOI: 10.1016/j.bcp.2014.01.003

    97. S. Salomone and F. Caraci: New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease- modifying drugs. Br J Clin Pharmacol, 73(4), 504-517 (2012)
    DOI: 10.1111/j.1365-2125.2011.04134.x

    98. K. E. Biron, D. L. Dickstein, R. Gopaul, W. A. Jefferies and B. Hendey: Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer’s Disease. PLoS One, 6, e23789 (2011)
    DOI: 10.1371/journal.pone.0023789

    99. L. Hedskog, C. M. Pinho, R. Filadi, A. Rönnbäck, L. Hertwig, B. Wiehager, P. Larssen, S. Gellhaar, A. Sandebring, M. Westerlund, C. Graff, B. Winblad, D. Galter, H. Behbahani, P. Pizzo, E. Glaser and M. Ankarcrona: Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci U S A, 110, 7916-21 (2013)
    DOI: 10.1073/pnas.1300677110

    100. Y. Miao, S. Zhao, Y. Gao, R. Wang, Q. Wu, H. Wu and T. Luo: Curcumin pretreatment attenuates inflammation and mitochondrial dysfunction in experimental stroke: The possible role of Sirt1 signaling. Brain Res Bull, 121, 9-15 (2016)
    DOI: 10.1016/j.brainresbull.2015.11.019

    101. E. S. Musiek and D. M. Holtzman: Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science, 354, 1004-1008 (2016)
    DOI: 10.1126/science.aah4968

    102. R. B. Narasingappa, M. R. Javagal, S. Pullabhatla, H. H. Htoo, J. K. Rao, J. F. Hernandez, P. Govitrapong and B. Vincent: Activation of alpha-secretase by curcumin-aminoacid conjugates. Biochem Biophys Res Commun, 424(4), 691-6 (2012)
    DOI: 10.1016/j.bbrc.2012.07.010

    103. O. Rom, H. Korach-Rechtman, T. Hayek, Y. Danin-Poleg, H. Bar, Y. Kashi and M. Aviram: Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: protective role for the polyphenol-rich pomegranate juice. Arch Toxicol, 91(4), 1709-1725 (2017)
    DOI: 10.1007/s00204-016-1859-8

    104. V. Singh, S. Roth, G. Llovera, R. Sadler, D. Garzetti, B. Stecher, M. Dichgans and A. Liesz: Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke. J Neurosci, 36 (2016)
    DOI: 10.1523/JNEUROSCI.1114-16.2016

    105. T. Yuan, H. Ma, W. Liu, D. B. Niesen, N. Shah, R. Crews, K. N. Rose, D. A. Vattem and N. P. Seeram: Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci, 7, 26-33 (2016)
    DOI: 10.1021/acschemneuro.5b00260

    106. N. D. Barnard, A. I. Bush, A. Ceccarelli, J. Cooper, C. A. de Jager, K. I. Erickson, G. Fraser, S. Kesler, S. M. Levin, B. Lucey, M. C. Morris and R. Squitti: Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease. Neurobiol Aging, 35 Suppl 2, S74-8 (2014)
    DOI: 10.1016/j.neurobiolaging.2014.03.033

    107. S. S. Kang, P. R. Jeraldo, A. Kurti, M. E. Miller, M. D. Cook, K. Whitlock, N. Goldenfeld, J. A. Woods, B. A. White, N. Chia and J. D. Fryer: Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener, 9, 36 (2014)
    DOI: 10.1186/1750-1326-9-36

    108. F. C. Lau, B. Shukitt-Hale and J. A. Joseph: The beneficial effects of fruit polyphenols on brain aging. Neurobiol Aging, 26 Suppl 1, 128-32 (2005)
    DOI: 10.1016/j.neurobiolaging.2005.08.007

    109. R. E. Hartman: Actions of Bioactive Phytochemicals in Cell Function and Alzheimer’s Disease Pathology. In: Micronutrients and Brain Health, 1-18 (2009)
    DOI: 10.1201/9781420073522.ch16

    110. A. I. Petra, S. Panagiotidou, E. Hatziagelaki, J. M. Stewart, P. Conti and T. C. Theoharides: Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation. Clin Ther, 37, 984-995 (2015)
    DOI: 10.1016/j.clinthera.2015.04.002

    111. Y. Zhao, P. Dua and W. J. Lukiw: Microbial Sources of Amyloid and Relevance to Amyloidogenesis and Alzheimer’s Disease (AD). J Alzheimers Dis Parkinsonism, 5, 177 (2015)

    112. H. Chen and S. Sang: Biotransformation of tea polyphenols by gut microbiota. J Funct Foods, 7, 26-42 (2014)
    DOI: 10.1016/j.jff.2014.01.013

    113. Y. S. Chiou, J. C. Wu, Q. Huang, F. Shahidi, Y. J. Wang, C. T. Ho and M. H. Pan: Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary polyphenols. J Funct Foods, 7, 3-25 (2014)
    DOI: 10.1016/j.jff.2013.08.006

    114. M. Gasperotti, S. Passamonti, F. Tramer, D. Masuero, G. Guella, F. Mattivi and U. Vrhovsek: Fate of Microbial Metabolites of Dietary Polyphenols in Rats: Is the Brain Their Target Destination? ACS Chem Neurosci, 6, 1341-1352 (2015)
    DOI: 10.1021/acschemneuro.5b00051

    115. L. Marin, E. M. Miguelez, C. J. Villar and F. Lombo: Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed Res Int, 2015, 905215 (2015)
    DOI: 10.1155/2015/905215

    116. S. G. Parkar, T. M. Trower and D. E. Stevenson: Fecal microbial metabolism of polyphenols and its effects on human gut microbiota. Anaerobe, 23, 12-19 (2013)
    DOI: 10.1016/j.anaerobe.2013.07.009

    117. D. Wang, L. Ho, J. Faith, K. Ono, E. M. Janle, P. J. Lachcik, B. R. Cooper, A. H. Jannasch, B. R. D’Arcy, B. A. Williams, M. G. Ferruzzi, S. Levine, W. Zhao, L. Dubner and G. M. Pasinetti: Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer’s disease β-amyloid oligomerization. Mol Nutr Food Res, 59, 1025-1040 (2015)
    DOI: 10.1002/mnfr.201400544

    118. T. F. Hughes, R. Andel, B. J. Small, A. R. Borenstein, J. A. Mortimer, A. Wolk, B. Johansson, L. Fratiglioni, N. L. Pedersen and M. Gatz: Midlife Fruit and Vegetable Consumption and Risk of Dementia in Later Life in Swedish Twins. Am J Geriatr Psychiatry, 18, 413-420 (2010)
    DOI: 10.1097/JGP.0b013e3181c65250

    119. S. E. Power, E. M. O’Connor, R. P. Ross, C. Stanton, P. W. O’Toole, G. F. Fitzgerald and I. B. Jeffery: Dietary glycaemic load associated with cognitive performance in elderly subjects. Eur J Nutr, 54, 557-68 (2015)
    DOI: 10.1007/s00394-014-0737-5

    120. Q. Dai, A. R. Borenstein, Y. Wu, J. C. Jackson and E. B. Larson: Fruit and Vegetable Juices and Alzheimer’s Disease: The Kame Project. Am J Med, 119, 751-759 (2006)
    DOI: 10.1016/j.amjmed.2006.03.045

    121. S. L. Gray, M. L. Anderson, P. K. Crane, J. C. Breitner, W. McCormick, J. D. Bowen, L. Teri and E. Larson: Antioxidant vitamin supplement use and risk of dementia or Alzheimer’s disease in older adults. J Am Geriatr Soc, 56(2), 291-5 (2008)
    DOI: 10.1111/j.1532-5415.2007.01531.x

    122. N. Farina, M. G. E. K. N. Isaac, A. R. Clark, J. Rusted and N. Tabet: Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev, 11, CD002854 (2012)
    DOI: 10.1002/14651858.CD002854.pub3

    123. L. Yuan, J. Liu, W. Ma, L. Dong, W. Wang, R. Che and R. Xiao: Dietary pattern and antioxidants in plasma and erythrocyte in patients with mild cognitive impairment from China. Nutrition, 32, 193-198 (2016)
    DOI: 10.1016/j.nut.2015.08.004

    124. V. Berti, J. Murray, M. Davies, N. Spector, W. H. Tsui, Y. Li, S. Williams, E. Pirraglia, S. Vallabhajosula, P. McHugh, A. Pupi, M. J. de Leon and L. Mosconi: Nutrient patterns and brain biomarkers of Alzheimer’s disease in cognitively normal individuals. J Nutr Health Aging, 19, 413-423 (2015)
    DOI: 10.1007/s12603-014-0534-0

    125. S. Lefèvre-Arbogast, C. Féart, J.-F. Dartigues, C. Helmer, L. Letenneur and C. Samieri: Dietary B Vitamins and a 10-Year Risk of Dementia in Older Persons. Nutrients, 8, 761 (2016)
    DOI: 10.3390/nu8120761

    126. N. Burkholder-Cooley, S. Rajaram, E. Haddad, G. E. Fraser and K. Jaceldo-Siegl: Comparison of polyphenol intakes according to distinct dietary patterns and food sources in the Adventist Health Study-2 cohort. Br J Nutr, 115(12), 2162-9 (2016)
    DOI: 10.1017/S0007114516001331

    127. R. J. Hardman, G. Kennedy, H. Macpherson, A. B. Scholey and A. Pipingas: Adherence to a Mediterranean-Style Diet and effects on Cognition in Adults: A Qualitative evaluation and Systematic Review of Longitudinal and Prospective Trials. Frontiers in Nutrit, 3, 1-13 (2016)
    DOI: 10.3389/fnut.2016.00022

    128. R. C. Robertson, C. Seira Oriach, K. Murphy, G. M. Moloney, J. F. Cryan, T. G. Dinan, R. Paul Ross and C. Stanton: Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood. Brain Behav Immun, 59, 21-37 (2016)
    DOI: 10.1016/j.bbi.2016.07.145

    129. C. Song, C. H. Shieh, Y. S. Wu, A. Kalueff, S. Gaikwad and K. P. Su: The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer’s disease: Acting separately or synergistically? Prog Lipid Res, 62, 41-54 (2016)
    DOI: 10.1016/j.plipres.2015.12.003

    130. M. Tavakkoli-Kakhki, M. Motavasselian, M. Mosaddegh, M. M. Esfahani, M. Kamalinejad, M. Nematy and S. Eslami: Omega-3 and omega-6 content of medicinal foods for depressed patients: implications from the Iranian Traditional Medicine. Avicenna J Phytomed, 4, 225-30 (2014)

    131. A. Trichopoulou, M. A. Martínez-González, T. Y. Tong, N. G. Forouhi, S. Khandelwal, D. Prabhakaran, D. Mozaffarian and M. de Lorgeril: Definitions and potential health benefits of the Mediterranean diet: views from experts around the world. BMC Med, 12, 112 (2014)
    DOI: 10.1186/1741-7015-12-112

    132. P. Sjögren, W. Becker, E. Warensjö, E. Olsson, L. Byberg, I. B. Gustafsson, B. Karlström and T. Cederholm: Mediterranean and carbohydrate-restricted diets and mortality among elderly men: A cohort study in Sweden. Am J Clin Nutr, 92, 967-974 (2010)
    DOI: 10.3945/ajcn.2010.29345

    133. C. Valls-Pedret, A. Sala-Vila, M. Serra-Mir, D. Corella, R. de la Torre, M. Á. Martínez-González, E. H. Martínez-Lapiscina, M. Fitó, A. Pérez-Heras, J. Salas-Salvadó, R. Estruch and E. Ros: Mediterranean Diet and Age-Related Cognitive Decline. JAMA Intern Med, 175, 1094 (2015)
    DOI: 10.1001/jamainternmed.2015.1668

    134. T. P. Ng, P. C. Chiam, T. Lee, H. C. Chua, L. Lim and E. H. Kua: Curry consumption and cognitive function in the elderly. Am J Epidemiol, 164(9), 898-906 (2006)
    DOI: 10.1093/aje/kwj267

    135. K. A. Arntzen, H. Schirmer, T. Wilsgaard and E. B. Mathiesen: Moderate wine consumption is associated with better cognitive test results: a 7-year follow up of 5033 subjects in the Tromsø Study. Acta Neurol Scand, 122, 23-29 (2010)
    DOI: 10.1111/j.1600-0404.2010.01371.x

    136. M. I. Covas, P. Gambert, M. Fitó and R. de la Torre: Wine and oxidative stress: Up-to-date evidence of the effects of moderate wine consumption on oxidative damage in humans. Atherosclerosis. 208(2), 297-304. (2010)
    DOI: 10.1016/j.atherosclerosis.2009.06.031

    137. J. M. Orgogozo, J. F. Dartigues, S. Lafont, L. Letenneur, D. Commenges, R. Salamon, S. Renaud and M. B. Breteler: Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris), 153, 185-192 (1997)

    138. J. A. Court, M. Johnson, D. Religa, J. Keverne, R. Kalaria, E. Jaros, I. G. McKeith, R. Perry, J. Naslund and E. K. Perry: Attenuation of Aβ deposition in the entorhinal cortex of normal elderly individuals associated with tobacco smoking. Neuropathol Appl Neurobiol, 31(5), 522-535 (2005)
    DOI: 10.1111/j.1365-2990.2005.00674.x

    139. S. Norton, F. E. Matthews, D. E. Barnes, K. Yaffe and C. Brayne: Potential for primary prevention of Alzheimer’s disease: An analysis of population-based data. The Lancet Neurol, 13, 788-794 (2014)
    DOI: 10.1016/S1474-4422(14)70136-X

    140. S. A. Farr, M. L. Niehoff, M. A. Ceddia, K. A. Herrlinger, B. J. Lewis, S. Feng, A. Welleford, D. A. Butterfield and J. E. Morley: Effect of botanical extracts containing carnosic acid or rosmarinic acid on learning and memory in SAMP8 mice. Physiol Behav, 165, 328-338 (2016)
    DOI: 10.1016/j.physbeh.2016.08.013

    141. R. Lucarini, W. A. Bernardes, D. S. Ferreira, M. G. Tozatti, R. Furtado, J. K. Bastos, P. M. Pauletti, A. H. Januário, M. L. A. e. Silva and W. R. Cunha: In vivo analgesic and anti-inflammatory activities of Rosmarinus officinalis aqueous extracts, rosmarinic acid and its acetyl ester derivative. Pharm Biol, 51, 1087-1090 (2013)
    DOI: 10.3109/13880209.2013.776613

    142. S. Rahman, R. A. Ansari, H. Rehman, S. Parvez and S. Raisuddin: Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin. Evid Based Complement Alternat Med, 2011, 734785 (2011)
    DOI: 10.1093/ecam/nep076

    143. V. Brezová, A. Šlebodová and A. Staško: Coffee as a source of antioxidants: An EPR study. Food Chem, 114, 859-868 (2009)
    DOI: 10.1016/j.foodchem.2008.10.025

    144. P. Esquivel and V. M. Jiménez: Functional properties of coffee and coffee by-products. Food Res Int, 46, 488-495 (2012)
    DOI: 10.1016/j.foodres.2011.05.028

    145. I. A. Ludwig, L. Sanchez, B. Caemmerer, L. W. Kroh, M. P. De Peña and C. Cid: Extraction of coffee antioxidants: Impact of brewing time and method. Food Res Int, 48, 57-64 (2012)
    DOI: 10.1016/j.foodres.2012.02.023

    146. J. A. Vignoli, D. G. Bassoli and M. T. Benassi: Antioxidant activity, polyphenols, caffeine and melanoidins in soluble coffee: The influence of processing conditions and raw material. Food Chem, 124, 863-868 (2011)
    DOI: 10.1016/j.foodchem.2010.07.008

    147. M. N. Braskie, N. Jahanshad, J. L. Stein, M. Barysheva, K. L. McMahon, G. I. de Zubicaray, N. G. Martin, M. J. Wright, J. M. Ringman, A. W. Toga and P. M. Thompson: Common Alzheimer’s disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci, 31(18), 6764-70 (2011)
    DOI: 10.1523/JNEUROSCI.5794-10.2011

    148. A. A. Reinke and J. E. Gestwicki: Structure–activity Relationships of Amyloid Beta-aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility. Chem Biol Drug Des, 70(3), 206-215 (2007)
    DOI: 10.1111/j.1747-0285.2007.00557.x

    149. J. M. Ringman, S. A. Frautschy, G. M. Cole, D. L. Masterman and J. L. Cummings: A potential role of the curry spice curcumin in Alzheimer’s disease. Curr Alzheimer Res, 2, 131-6 (2005)
    DOI: 10.2174/1567205053585882

    150. K. Ono, K. Hasegawa, H. Naiki and M. Yamada: Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res, 75, 742-750 (2004)
    DOI: 10.1002/jnr.20025

    151. F. Yang, G. P. Lim, A. N. Begum, O. J. Ubeda, M. R. Simmons, S. S. Ambegaokar, P. P. Chen, R. Kayed, C. G. Glabe, S. A. Frautschy and G. M. Cole: Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem, 280(7), 5892-901 (2005)
    DOI: 10.1074/jbc.M404751200

    152. S. A. Frautschy, W. Hu, P. Kim, S. A. Miller, T. Chu, M. E. Harris-White and G. M. Cole: Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology. Neurobiol Aging, 22, 993-1005 (2001)
    DOI: 10.1016/S0197-4580(01)00300-1

    153. G. P. Lim, T. Chu, F. Yang, W. Beech, S. a. Frautschy and G. M. Cole: The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci, 21, 8370-8377 (2001)

    154. M. D. Laird, S. Sukumari-Ramesh, A. E. Swift, S. E. Meiler, J. R. Vender and K. M. Dhandapani: Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem, 113(3), 637-48 (2010)
    DOI: 10.1111/j.1471-4159.2010.06630.x

    155. P. Thomas, Y. J. Wang, J. H. Zhong, S. Kosaraju, N. J. O’Callaghan, X. F. Zhou and M. Fenech: Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer’s disease. Mutat Res, 661(1-2), 25-34 (2009)
    DOI: 10.1016/j.mrfmmm.2008.10.016

    156. K. M. Seong, M. Yu, K. S. Lee, S. Park, Y. W. Jin and K. J. Min: Curcumin mitigates accelerated aging after irradiation in Drosophila by reducing oxidative stress. Biomed Res Int, 2015, 425380 (2015)
    DOI: 10.1155/2015/425380

    157. J. R. Santos-Parker, T. R. Strahler, C. J. Bassett, N. Z. Bispham, B. Michel and D. R. Seals: Curcumin supplementation improves vascular endothelial function in healthy middle aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging, 9, 1-22 (2016)
    DOI: 10.18632/aging.101149

    158. B. B. Aggarwal and S. Shishodia: Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci, 1030, 434-41 (2004)
    DOI: 10.1196/annals.1329.054

    159. B. B. Aggarwal and S. Shishodia: Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol, 71(10), 1397-421 (2006)
    DOI: 10.1016/j.bcp.2006.02.009

    160. D. Rai, Jay K. Singh, N. Roy and D. Panda: Curcumin inhibits FtsZ assembly: an attractive mechanism for its antibacterial activity. Biochem J, 410 (2008)
    DOI: 10.1042/BJ20070891

    161. P. Kumaraswamy, S. Sethuraman and U. M. Krishnan: Mechanistic Insights of Curcumin Interactions with the Core-Recognition Motif of β-Amyloid Peptide. J Agric Food Chem, 61, 3278-3285 (2013)
    DOI: 10.1021/jf4000709

    162. P. Ambigaipalan, A. C. de Camargo and F. Shahidi: Phenolic Compounds of Pomegranate Byproducts (Outer Skin, Mesocarp, Divider Membrane) and Their Antioxidant Activities. J Agric Food Chem, 64(34), 6584-604 (2016)
    DOI: 10.1021/acs.jafc.6b02950

    163. W. Elfalleh, N. Tlili, N. Nasri, Y. Yahia, H. Hannachi, N. Chaira, M. Ying and A. Ferchichi: Antioxidant capacities of phenolic compounds and tocopherols from Tunisian pomegranate (Punica granatum) fruits. J Food Sci, 76(5), C707-13 (2011)
    DOI: 10.1111/j.1750-3841.2011.02179.x

    164. D. Heber: Pomegranate Ellagitannins. In: Herbal Medicine: Biomolecular and Clinical Aspects, 1-9 (2011)
    DOI: 10.1201/b10787-11

    165. S. D. Johanningsmeier and G. K. Harris: Pomegranate as a functional food and nutraceutical source. Annu Rev Food Sci Technol, 2, 181-201 (2011)
    DOI: 10.1146/annurev-food-030810-153709

    166. M. Larrosa, A. Gonzalez-Sarrias, M. J. Yanez-Gascon, M. V. Selma, M. Azorin-Ortuno, S. Toti, F. Tomas-Barberan, P. Dolara and J. C. Espin: Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem, 21(8), 717-25 (2010)
    DOI: 10.1016/j.jnutbio.2009.04.012

    167. P. Legua, P. Melgarejo, H. Abdelmajid, J. J. Martinez, R. Martinez, H. Ilham, H. Hafida and F. Hernandez: Total phenols and antioxidant capacity in 10 Moroccan pomegranate varieties. J Food Sci, 77(1), C115-20 (2012)
    DOI: 10.1111/j.1750-3841.2011.02516.x

    168. A. Masci, A. Coccia, E. Lendaro, L. Mosca, P. Paolicelli and S. Cesa: Evaluation of different extraction methods from pomegranate whole fruit or peels and the antioxidant and antiproliferative activity of the polyphenolic fraction. Food Chem, 202, 59-69 (2016)
    DOI: 10.1016/j.foodchem.2016.01.106

    169. S. Sreekumar, H. Sithul, P. Muraleedharan, J. M. Azeez and S. Sreeharshan: Pomegranate fruit as a rich source of biologically active compounds. Biomed Res Int, 2014, 686921 (2014)
    DOI: 10.1155/2014/686921

    170. C. Venkata, S. Prakash and I. Prakash: Bioactive Chemical Constituents from Pomegranate (Punica granatum) Juice, Seed and Peel-A Review. Int J Res Chem Environ, 1, 1-181 (2011)

    171. R. Wang, Y. Ding, R. Liu, L. Xiang and L. Du: Pomegranate: Constituents , Bioactivities and Pharmacokinetics. Fruit, Veg Cereal Sci Biotech, 4, 77-87 (2010)

    172. H. M. Al-Kuraishy and A. I. Al-Gareeb: Potential Effects of Pomegranate on Lipid Peroxidation and Pro-inflammatory Changes in Daunorubicin-induced Cardiotoxicity in Rats. Int J Prev Med, 7, 85 (2016)
    DOI: 10.4103/2008-7802.184314

    173. L. A. BenSaad, K. H. Kim, C. C. Quah, W. R. Kim and M. Shahimi: Anti-inflammatory potential of ellagic acid, gallic acid and punicalagin A&B isolated from Punica granatum. BMC Complement Altern Med, 17(1), 47 (2017)
    DOI: 10.1186/s12906-017-1555-0

    174. A. Bishayee, D. Bhatia, R. J. Thoppil, A. S. Darvesh, E. Nevo and E. P. Lansky: Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis, 32(6), 888-96 (2011)
    DOI: 10.1093/carcin/bgr045

    175. A. Bishayee, R. J. Thoppil, A. S. Darvesh, V. Ohanyan, J. G. Meszaros and D. Bhatia: Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis. J Nutr Biochem, 24(1), 178-87 (2013) doi:10.1.016/j.jnutbio.2012.0.4.0.09
    DOI: 10.1016/j.jnutbio.2012.04.009

    176. M. Cano-Lamadrid, F. C. Marhuenda-Egea, F. Hernandez, E. C. Rosas-Burgos, A. Burgos-Hernandez and A. A. Carbonell-Barrachina: Biological Activity of Conventional and Organic Pomegranate Juices: Antioxidant and Antimutagenic Potential. Plant Foods Hum Nutr, 71(4), 375-380 (2016)
    DOI: 10.1007/s11130-016-0569-y

    177. A. Husari, Y. Hashem, H. Bitar, G. Dbaibo, G. Zaatari and M. El Sabban: Antioxidant activity of pomegranate juice reduces emphysematous changes and injury secondary to cigarette smoke in an animal model and human alveolar cells. Int J Chron Obstruct Pulmon Dis, 11, 227-37 (2016)
    DOI: 10.2147/COPD.S97027

    178. C. M. Matthaiou, N. Goutzourelas, D. Stagos, E. Sarafoglou, A. Jamurtas, S. D. Koulocheri, S. A. Haroutounian, A. M. Tsatsakis and D. Kouretas: Pomegranate juice consumption increases GSH levels and reduces lipid and protein oxidation in human blood. Food Chem Toxicol, 73, 1-6 (2014)
    DOI: 10.1016/j.fct.2014.07.027

    179. S. U. Mertens-Talcott, P. Jilma-Stohlawetz, J. Rios, L. Hingorani and H. Derendorf: Absorption, Metabolism, and Antioxidant Effects of Pomegranate ( Punica granatumL.) Polyphenols after Ingestion of a Standardized Extract in Healthy Human Volunteers. J Agric Food Chem, 54, 8956-8961 (2006)
    DOI: 10.1021/jf061674h

    180. M. Aviram, L. Dornfeld, M. Rosenblat, N. Volkova, M. Kaplan, T. Hayek, D. Presser and B. Fuhrman: Pomegranate juice consumption reduces oxidative stress and low density lipoprotein atherogenic modifications: studies in the atherosclerotic apolipoprotein E deficient mice and in humans. The Am J Clin Nutr, 151, 111 (2000)

    181. M. Kaplan, T. Hayek, a. Raz, R. Coleman, L. Dornfeld, J. Vaya and M. Aviram: Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. J Nutr, 131, 2082-2089 (2001)

    182. M. Aviram, M. Rosenblat, D. Gaitini, S. Nitecki, A. Hoffman, L. Dornfeld, N. Volkova, D. Presser, J. Attias, H. Liker and T. Hayek: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr, 23(3), 423-33 (2004)
    DOI: 10.1016/j.clnu.2003.10.002

    183. O. Rozenberg, A. Howell and M. Aviram: Pomegranate juice sugar fraction reduces macrophage oxidative state, whereas white grape juice sugar fraction increases it. Atherosclerosis, 188(1), 68-76 (2006)
    DOI: 10.1016/j.atherosclerosis.2005.10.027

    184. F. de Nigris, S. Williams-Ignarro, L. O. Lerman, E. Crimi, C. Botti, G. Mansueto, F. P. D’Armiento, G. De Rosa, V. Sica, L. J. Ignarro and C. Napoli: Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress. Proc Natl Acad Sci U S A, 102, 4896-901 (2005)
    DOI: 10.1073/pnas.0500998102

    185. N. P. Seeram, L. S. Adams, S. M. Henning, Y. Niu, Y. Zhang, M. G. Nair and D. Heber: In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem, 16(6), 360-7 (2005)
    DOI: 10.1016/j.jnutbio.2005.01.006

    186. M. Rosenblat, N. Volkova, R. Coleman and M. Aviram: Pomegranate byproduct administration to apolipoprotein E-deficient mice attenuates atherosclerosis development as a result of decreased macrophage oxidative stress and reduced cellular uptake of oxidized low-density lipoprotein. J Agric Food Chem, 54, 1928-1935 (2006)
    DOI: 10.1021/jf0528207

    187. L. S. Adams, N. P. Seeram, B. B. Aggarwal, Y. Takada, D. Sand and D. Heber: Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem, 54, 980-985 (2006)
    DOI: 10.1021/jf052005r

    188. L. G. Chen, Y. C. Liu, C. W. Hsieh, B. C. Liao and B. S. Wung: Tannin 1-alpha-O-galloylpunicalagin induces the calcium-dependent activation of endothelial nitric-oxide synthase via the phosphatidylinositol 3-kinase/Akt pathway in endothelial cells. Mol Nutr Food Res, 52(10), 1162-71 (2008)
    DOI: 10.1002/mnfr.200700335

    189. M. Ghavipour, G. Sotoudeh, E. Tavakoli, K. Mowla, J. Hasanzadeh and Z. Mazloom: Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation and oxidative stress in Rheumatoid Arthritis patients. Eur J Clin Nutr, 71(1), 92-96 (2017)
    DOI: 10.1038/ejcn.2016.151

    190. D. J. Loren, N. P. Seeram, R. N. Schulman and D. M. Holtzman: Maternal dietary supplementation with pomegranate juice is neuroprotective in an animal model of neonatal hypoxic-ischemic brain injury. Pediatr Res, 57(6), 858-64 (2005)
    DOI: 10.1203/01.PDR.0000157722.07810.15

    191. H.-M. Kwak, S.-Y. Jeon, B.-H. Sohng, J.-G. Kim, J.-M. Lee, K.-B. Lee, H.-H. Jeong, J.-M. Hur, Y.-H. Kang and K.-S. Song: β-Secretase(BACE1) inhibitors from pomegranate (Punica granatum) husk. Arch Pharm Res, 28(12), 1328-1332 (2005)
    DOI: 10.1007/BF02977896

    192. M. C. Morzelle, J. M. Salgado, M. Telles, D. Mourelle, P. Bachiega, H. S. Buck and T. A. Viel: Neuroprotective Effects of Pomegranate Peel Extract after Chronic Infusion with Amyloid-beta Peptide in Mice. PLoS One, 11(11), e0166123 (2016)
    DOI: 10.1371/journal.pone.0166123

    193. L. Rojanathammanee, K. L. Puig and C. K. Combs: Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease. J Nutr, 143, 597-605 (2013)
    DOI: 10.3945/jn.112.169516

    194. S. Subash, N. Braidy, M. M. Essa, A. B. Zayana, V. Ragini, S. Al-Adawi, A. Al-Asmi and G. J. Guillemin: Long-term (15mo) dietary supplementation with pomegranates from Oman attenuates cognitive and behavioral deficits in a transgenic mice model of Alzheimer’s disease. Nutrition, 31, 223-229 (2015)
    DOI: 10.1016/j.nut.2014.06.004

    195. M. S. Dulcich and R. E. Hartman: Pomegranate supplementation improves affective and motor behavior in mice after radiation exposure. Evid Based Complement Alternat Med, 2013, 940830 (2013)
    DOI: 10.1155/2013/940830

    196. S. A. Ropacki, S. M. Patel and R. E. Hartman: Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study. Evid Based Complement Alternat Med, 2013, 932401 (2013)
    DOI: 10.1155/2013/932401

    197. S. Y. Bookheimer, B. A. Renner, A. Ekstrom, Z. Li, S. M. Henning, J. A. Brown, M. Jones, T. Moody and G. W. Small: Pomegranate juice augments memory and FMRI activity in middle-aged and older adults with mild memory complaints. Evid Based Complement Alternat Med, 2013, 946298 (2013)
    DOI: 10.1155/2013/946298

    198. N. P. Seeram, S. M. Henning, Y. Zhang, M. Suchard, Z. Li and D. Heber: Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr, 136, 2481-2485 (2006)

    199. J. C. Espin, M. Larrosa, M. T. Garcia-Conesa and F. Tomas-Barberan: Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med, 2013, 270418 (2013)
    DOI: 10.1155/2013/270418

    200. T. Yuan, H. Ma, W. Liu, D. B. Niesen, N. Shah, R. Crews, K. N. Rose, D. A. Vattem and N. P. Seeram: Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci, 7(1), 26-33 (2016)
    DOI: 10.1021/acschemneuro.5b00260

    201. M. A. Ahmed, E. M. El Morsy and A. A. Ahmed: Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats. Life Sci, 110(2), 61-9 (2014)
    DOI: 10.1016/j.lfs.2014.06.023

    202. K. Cao, J. Xu, W. Pu, Z. Dong, L. Sun, W. Zang, F. Gao, Y. Zhang, Z. Feng and J. Liu: Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation. Sci Rep, 5, 14014 (2015)
    DOI: 10.1038/srep14014

    203. R. Chavez-Valdez, L. J. Martin and F. J. Northington: Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury. Neurol Res Int, 2012, 257563 (2012)
    DOI: 10.1155/2012/257563

    204. A. B. Howell and D. H. D. Souza: The pomegranate : effects on bacteria and viruses that influence human health effects on human bacteria bacteria that affect the human body. Evid Based Complement Alternat Med, 2013 (2013)
    DOI: 10.1155/2013/606212

    205. A. Riaz and R. A. Khan: Anticoagulant, antiplatelet and antianemic effects of Punica granatum (pomegranate) juice in rabbits. Blood Coagul Fibrinolysis, 27(3), 287-93 (2016)
    DOI: 10.1097/MBC.0000000000000415

    206. N. M. Shafik and M. M. El Batsh: Protective Effects of Combined Selenium and Punica granatum Treatment on Some Inflammatory and Oxidative Stress Markers in Arsenic-Induced Hepatotoxicity in Rats. Biol Trace Elem Res, 169(1), 121-8 (2016)
    DOI: 10.1007/s12011-015-0397-1

    207. D. N. Syed, J.-C. Chamcheu, V. M. Adhami and H. Mukhtar: Pomegranate extracts and cancer prevention: molecular and cellular activities. Anticancer Agents Med Chem, 13, 1149-61 (2013)
    DOI: 10.2174/1871520611313080003

    208. L. Wang, W. Li, M. Lin, M. Garcia and D. Mulholland: Luteolin, Ellagic Acid and Punicic Acid are Natural Products that Inhibit Prostate Cancer Metastasis. Carcinogenesis, 35(10), 2321-2330. (2014)
    DOI: 10.1093/carcin/bgu145

    209. L. C. Braga, J. W. Shupp, C. Cummings, M. Jett, J. A. Takahashi, L. S. Carmo, E. Chartone-Souza and A. M. Nascimento: Pomegranate extract inhibits Staphylococcus aureus growth and subsequent enterotoxin production. J Ethnopharmacol, 96(1-2), 335-9 (2005)
    DOI: 10.1016/j.jep.2004.08.034

    210. S. S. Karuppagounder, J. T. Pinto, H. Xu, H. L. Chen, M. F. Beal and G. E. Gibson: Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int, 54, 111-118 (2009)
    DOI: 10.1016/j.neuint.2008.10.008

    211. H. Capiralla, V. Vingtdeux, H. Zhao, R. Sankowski, Y. Al-Abed, P. Davies and P. Marambaud: Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J Neurochem, 120, 461-472 (2012)
    DOI: 10.1111/j.1471-4159.2011.07594.x

    212. T. Köbe, A. V. Witte, A. Schnelle, V. A. Tesky, J. Pantel, J.-P. Schuchardt, A. Hahn, J. Bohlken, U. Grittner and A. Flöel: Impact of Resveratrol on Glucose Control, Hippocampal Structure and Connectivity, and Memory Performance in Patients with Mild Cognitive Impairment. Front Neurosci, 11 (2017)
    DOI: 10.3389/fnins.2017.00105

    213. D. Porquet, C. Griñán-Ferré, I. Ferrer, A. Camins, C. Sanfeliu, J. Del Valle and M. Pallàs: Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease. J Alzheimers Dis, 42, 1209-20 (2014)

    214. O. Ates, S. Cayli, E. Altinoz, I. Gurses, N. Yucel, M. Sener, A. Kocak and S. Yologlu: Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem, 294(1-2), 137-44 (2007)
    DOI: 10.1007/s11010-006-9253-0

    215. D. Wan, Y. Zhou, K. Wang, Y. Hou, R. Hou and X. Ye: Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP/AMPK/SIRT1 pathway after stroke in rats. Brain Res Bull, 121, 255-62 (2016)
    DOI: 10.1016/j.brainresbull.2016.02.011

    216. T. West, M. Atzeva and D. M. Holtzman: Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury. Dev Neurosci, 29(4-5), 363-72 (2007)
    DOI: 10.1159/000105477

    217. I. C. Burckhardt, D. Gozal, E. Dayyat, Y. Cheng, R. C. Li, A. D. Goldbart and B. W. Row: Green tea catechin polyphenols attenuate behavioral and oxidative responses to intermittent hypoxia. Am J Respir Crit Care Med, 177(10), 1135-41 (2008)
    DOI: 10.1164/rccm.200701-110OC

    218. Y. Xu, J.-j. Zhang, L. Xiong, L. Zhang, D. Sun and H. Liu: Green tea polyphenols inhibit cognitive impairment induced by chronic cerebral hypoperfusion via modulating oxidative stress. J Nutr Biochem, 21, 741-748 (2010)
    DOI: 10.1016/j.jnutbio.2009.05.002

    219. D. B. Mathiyazahan, A. Justin Thenmozhi and T. Manivasagam: Protective effect of black tea extract against aluminium chloride-induced Alzheimer’s disease in rats: A behavioural, biochemical and molecular approach. J Funct Foods, 16, 423-435 (2015)
    DOI: 10.1016/j.jff.2015.05.001

    220. H. J. Lim, S. B. Shim, S. W. Jee, S. H. Lee, C. J. Lim, J. T. Hong, Y. Y. Sheen and D. Y. Hwang: Green tea catechin leads to global improvement among Alzheimer’s disease-related phenotypes in NSE/hAPP-C105 Tg mice. J Nutr Biochem, 24, 1302-1313 (2013)
    DOI: 10.1016/j.jnutbio.2012.10.005

    221. N. Dragicevic, A. Smith, X. Lin, F. Yuan, N. Copes, V. Delic, J. Tan, C. Cao, R. D. Shytle and P. C. Bradshaw: Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction. J Alzheimers Dis, 26, 507-521 (2011)

    222. J. Rodrigues, M. Assunção, N. Lukoyanov, A. Cardoso, F. Carvalho and J. P. Andrade: Protective effects of a catechin-rich extract on the hippocampal formation and spatial memory in aging rats. Behav Brain Res, 246, 94-102 (2013)
    DOI: 10.1016/j.bbr.2013.02.040

    223. M. Giacalone, F. Di Sacco, I. Traupe, N. Pagnucci, F. Forfori and F. Giunta: Blueberry Polyphenols and Neuroprotection. In: Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease. Elsevier, (2015)
    DOI: 10.1016/B978-0-12-411462-3.00002-3

    224. D. H. Malin, D. R. Lee, P. Goyarzu, Y.-H. Chang, L. J. Ennis, E. Beckett, B. Shukitt-Hale and J. A. Joseph: Basic nutritional investigation Short-term blueberry-enriched diet prevents and reverses object recognition memory loss in aging rats. Nutrition, 27, 338-342 (2011)
    DOI: 10.1016/j.nut.2010.05.001

    225. M. Sousa, V. H. Teixeira and J. Soares: Dietary strategies to recover from exercise-induced muscle damage. Int J Food Sci Nutr, 65(2), 151-163 (2014)
    DOI: 10.3109/09637486.2013.849662

    226. K. B. Duffy, E. L. Spangler, B. D. Devan, Z. Guo, J. L. Bowker, A. M. Janas, A. Hagepanos, R. K. Minor, R. DeCabo, P. R. Mouton, B. Shukitt-Hale, J. A. Joseph and D. K. Ingram: A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats. Neurobiol Aging, 29, 1680-1689 (2008)
    DOI: 10.1016/j.neurobiolaging.2007.04.002

    227. M. A. Papandreou, A. Dimakopoulou, Z. I. Linardaki, P. Cordopatis, D. Klimis-Zacas, M. Margarity and F. N. Lamari: Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activity. Behav Brain Res, 198, 352-358 (2009)
    DOI: 10.1016/j.bbr.2008.11.013

    228. C. M. Williams, M. A. El Mohsen, D. Vauzour, C. Rendeiro, L. T. Butler, J. A. Ellis, M. Whiteman and J. P. E. Spencer: Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med, 45, 295-305 (2008)
    DOI: 10.1016/j.freeradbiomed.2008.04.008

    229. A. R. Whyte and C. M. Williams: Effects of a single dose of a flavonoid-rich blueberry drink on memory in 8 to 10y old children. Nutrition, 31, 531-534 (2015)
    DOI: 10.1016/j.nut.2014.09.013

    230. H. Wang, H. Wang, H. Cheng and Z. Che: Ameliorating effect of luteolin on memory impairment in an Alzheimer’s disease model. Mol Med Rep, 13, 4215-4220 (2016)
    DOI: 10.3892/mmr.2016.5052

    231. T.-X. Yu, P. Zhang, Y. Guan, M. Wang and M.-Q. Zhen: Protective effects of luteolin against cognitive impairment induced by infusion of Aβ peptide in rats. Int J Clin Exp Pathol, 8, 6740-7 (2015)

    232. D. Sawmiller, S. Li, M. Shahaduzzaman, A. Smith, D. Obregon, B. Giunta, C. Borlongan, P. Sanberg and J. Tan: Luteolin Reduces Alzheimer’s Disease Pathologies Induced by Traumatic Brain Injury. Int J Mol Sci, 15, 895-904 (2014)
    DOI: 10.3390/ijms15010895

    233. R. Liu, M. Gao, G.-F. Qiang, T.-T. Zhang, X. Lan, J. Ying and G.-H. Du: The anti-amnesic effects of luteolin against amyloid β25–35 peptide-induced toxicity in mice involve the protection of neurovascular unit. Neuroscience, 162, 1232-1243 (2009)
    DOI: 10.1016/j.neuroscience.2009.05.009

    234. F. Zhou, S. Chen, J. Xiong, Y. Li and L. Qu: Luteolin reduces zinc-induced tau phosphorylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biol Trace Elem Res, 149, 273-279 (2012
    DOI: 10.1007/s12011-012-9411-z

    235. Y. Liu, X. Fu, N. Lan, S. Li, J. Zhang, S. Wang, C. Li, Y. Shang, T. Huang and L. Zhang: Luteolin protects against high fat diet-induced cognitive deficits in obesity mice. Behav Brain Res, 267, 178-188 (2014)
    DOI: 10.1016/j.bbr.2014.02.040

    236. J.-X. Zhang, J.-G. Xing, L.-L. Wang, H.-L. Jiang, S.-L. Guo and R. Liu: Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways. Molecules, 22, 334 (2017)
    DOI: 10.3390/molecules22030334

    237. D.-J. Guo, F. Li, P. H.-F. Yu and S.-W. Chan: Neuroprotective effects of luteolin against apoptosis induced by 6-hydroxydopamine on rat pheochromocytoma PC12 cells. Pharm Biol, 51, 190-196 (2013)
    DOI: 10.3109/13880209.2012.716852

    238. D. Yu, M. Li, Y. Tian, J. Liu and J. Shang: Luteolin inhibits ROS-activated MAPK pathway in myocardial ischemia/reperfusion injury. Life Sciences, 122, 15-25 (2015)
    DOI: 10.1016/j.lfs.2014.11.014

    239. P. Pratheeshkumar, Y.-O. Son, S. P. Divya, R. V. Roy, J. A. Hitron, L. Wang, D. Kim, J. Dai, P. Asha, Z. Zhang, Y. Wang and X. Shi: Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways. Toxicol Appl Pharmacol, 281, 230-241 (2014)
    DOI: 10.1016/j.taap.2014.10.008

    240. D. Prakash, K. Gopinath and G. Sudhandiran: Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. Neuromolecular Med, 15, 192-208 (2013)
    DOI: 10.1007/s12017-012-8210-1

    241. X.-T. Hu, C. Ding, N. Zhou and C. Xu: Quercetin protects gastric epithelial cell from oxidative damage in vitro and in vivo. Eur J Pharmacol, 754, 115-124 (2015)
    DOI: 10.1016/j.ejphar.2015.02.007

    242. M. Ramezani, N. Darbandi, F. Khodagholi and A. Hashemi: Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer’s disease. Neural Regen Res, 11, 1976-1980 (2016)
    DOI: 10.4103/1673-5374.197141

    243. H. Herrschaft, A. Nacu, S. Likhachev, I. Sholomov, R. Hoerr and S. Schlaefke: Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res, 46, 716-723 (2012)
    DOI: 10.1016/j.jpsychires.2012.03.003

    244. R. Ihl, M. Tribanek and N. Bachinskaya: Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761 in Alzheimer’s Disease and vascular dementia: Results from a randomised controlled trial. Pharmacopsychiatry, 45, 41-46 (2012)
    DOI: 10.1055/s-0031-1291217

    245. O. Napryeyenko, G. Sonnik and I. Tartakovsky: Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: Analyses of a randomised controlled trial. J Neurol Sci, 283, 224-229 (2009)
    DOI: 10.1016/j.jns.2009.02.353

    246. H. Amieva, C. Meillon, C. Helmer, P. Barberger-Gateau and J. F. Dartigues: Ginkgo Biloba Extract and Long-Term Cognitive Decline: A 20-Year Follow-Up Population-Based Study. PLoS One, 8, e52755 (2013)
    DOI: 10.1371/journal.pone.0052755

    247. B. Vellas, N. Coley, P. J. Ousset, G. Berrut, J. F. o. Dartigues, B. Dubois, H. l. n. Grandjean, F. Pasquier, F. o. Piette, P. Robert, J. Touchon, P. Garnier, H. l. n. Mathiex-Fortunet and S. Andrieu: Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomised placebo-controlled trial. The Lancet Neurol, 11, 851-859 (2012)
    DOI: 10.1016/S1474-4422(12)70206-5

    248. L. S. Schneider: Ginkgo and AD: Key negatives and lessons from GuidAge. The Lancet Neurol, 11(10), 836 (2012)
    DOI: 10.1016/S1474-4422(12)70212-0

    249. T. Yoshitake, S. Yoshitake and J. Kehr: The Ginkgo biloba extract EGb 761(R) and its main constituent flavonoids and ginkgolides increase extracellular dopamine levels in the rat prefrontal cortex. Br J Pharmacol, 159, 659-668 (2010)
    DOI: 10.1111/j.1476-5381.2009.00580.x

    250. M. Belviranlı and N. Okudan: The effects of Ginkgo biloba extract on cognitive functions in aged female rats: The role of oxidative stress and brain-derived neurotrophic factor. Behav Brain Res, 278, 453-461 (2014)
    DOI: 10.1016/j.bbr.2014.10.032

    251. E. A. Tendi, F. Bosetti, S. F. DasGupta, A. M. Giuffrida Stella, K. Drieu and S. I. Rapoport: Ginkgo biloba Extracts EGb 761 and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells. Neurochem Res, 27(4), 319-323 (2002)
    DOI: 10.1023/A:1014963313559

    252. P. Rojas, N. Serrano-García, J. J. Mares-Sámano, O. N. Medina-Campos, J. Pedraza-Chaverri and S. O. Ögren: EGb761 protects against nigrostriatal dopaminergic neurotoxicity in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced Parkinsonism in mice: Role of oxidative stress. European J Neurosci, 28, 41-50 (2008)
    DOI: 10.1111/j.1460-9568.2008.06314.x

    253. S. Yancheva, R. Ihl, G. Nikolova, P. Panayotov, S. Schlaefke and R. Hoerr: Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer’s disease with neuropsychiatric features: a randomised, double-blind, exploratory trial. Aging Ment Health, 13, 183-90 (2009)
    DOI: 10.1080/13607860902749057

    254. S. Weinmann, S. Roll, C. Schwarzbach, C. Vauth and S. N. Willich: Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr, 10(1), 14 (2010)
    DOI: 10.1186/1471-2318-10-14

    255. F. Tchantchou, Y. Xu, Y. Wu, Y. Christen and Y. Luo: EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. FASEB J, 21(10), 2400-8 (2007)
    DOI: 10.1096/fj.06-7649com

    256. X. Liu, W. Hao, Y. Qin, Y. Decker, X. Wang, M. Burkart, K. Schötz, M. D. Menger, K. Fassbender and Y. Liu: Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer’s disease. Brain Behav Immun, 46, 121-131 (2015)
    DOI: 10.1016/j.bbi.2015.01.011

    257. A. Eckert: Mitochondrial effects of Ginkgo biloba extract. Int Psychogeriatr, 24, S18-S20 (2012)
    DOI: 10.1017/S1041610212000531

    258. W. E. Müller, J. Heiser and K. Leuner: Effects of the standardized Ginkgo biloba extract EGb 761® on neuroplasticity. Int Psychogeriatr, 24 Suppl 1, S21-4 (2012)
    DOI: 10.1017/S1041610212000592

    259. L. Rangel-Ordóñez, M. Nöldner, M. Schubert-Zsilavecz and M. Wurglics: Plasma levels and distribution of flavonoids in rat brain after single and repeated doses of standardized Ginkgo biloba extract EGb 761. Planta Med, 76, 1683-1690 (2010)
    DOI: 10.1055/s-0030-1249962

    260. O. Vitolo, B. Gong, Z. Cao, H. Ishii, S. Jaracz, K. Nakanishi, O. Arancio, S. V. Dzyuba, R. Lefort and M. Shelanski: Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J. Neurobiol Aging, 30, 257-265 (2009)
    DOI: 10.1016/j.neurobiolaging.2007.05.025

    261. T. Ma, K. Gong, Y. Yan, L. Zhang, P. Tang, X. Zhang and Y. Gong: Huperzine A promotes hippocampal neurogenesis in vitro and in vivo. Brain Res, 1506, 35-43 (2013)
    DOI: 10.1016/j.brainres.2013.02.026

    262. X. Gao, C. Y. Zheng, L. Yang, X. C. Tang and H. Y. Zhang: Huperzine A protects isolated rat brain mitochondria against β-amyloid peptide. Free Radic Biol Med, 46, 1454-1462 (2009)
    DOI: 10.1016/j.freeradbiomed.2009.02.028

    263. X. Ma and D. R. Gang: In vitro production of huperzine A, a promising drug candidate for Alzheimer’s disease. Phytochemistry, 69, 2022-2028 (2008)
    DOI: 10.1016/j.phytochem.2008.04.017

    264. M. Ratia, L. Giménez-Llort, P. Camps, D. Muñoz-Torrero, B. Pérez, M. V. Clos and A. Badia: Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD). Neurodegener Dis, 11, 129-140 (2013)
    DOI: 10.1159/000336427

    265. M. S. Rafii, S. Walsh, J. T. Little, K. Behan, B. Reynolds, C. Ward, S. Jin, R. Thomas, P. S. Aisen and F. t. A. s. D. C. Alzheimer’s Disease Cooperative Study: A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology, 76, 1389-94 (2011)
    DOI: 10.1212/WNL.0b013e318216eb7b

    266. M. Haghani, M. Shabani, M. Javan, F. Motamedi and M. Janahmadi: CB1 cannabinoid receptor activation rescues amyloid β-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal CA1 pyramidal neurones. Cell Physiol Biochem, 29, 391-406 (2012)
    DOI: 10.1159/000338494

    267. B. S. Harvey, K. S. Ohlsson, J. L. V. Mååg, I. F. Musgrave and S. D. Smid: Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro. Neurotoxicology, 33, 138-146 (2012)
    DOI: 10.1016/j.neuro.2011.12.015

    268. C. Cao, Y. Li, H. Liu, G. Bai, J. Mayl, X. Lin, K. Sutherland, N. Nabar and J. Cai: The potential therapeutic effects of THC on Alzheimer’s disease. J Alzheimers Dis, 42, 973-84 (2014)

    269. S. A. Wolf, A. Bick-Sander, K. Fabel, P. Leal-Galicia, S. Tauber, G. Ramirez-Rodriguez, A. Müller, A. Melnik, T. P. Waltinger, O. Ullrich and G. Kempermann: Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun Signal, 8, 12 (2010)
    DOI: 10.1186/1478-811X-8-12

    270. W. Jiang: Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest, 115, 3104-3116 (2005)
    DOI: 10.1172/JCI25509

    271. T. Bisogno and V. Di Marzo: Cannabinoid Receptors and Endocannabinoids: Role in Neuroinflammatory and Neurodegenerative Disorders. CNS Neurol Disord Drug Targets, 9, 564-573 (2010)
    DOI: 10.2174/187152710793361568

    272. Y. Marchalant, H. M. Brothers, G. J. Norman, K. Karelina, A. C. DeVries and G. L. Wenk: Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis, 34, 300-307 (2009)
    DOI: 10.1016/j.nbd.2009.01.014

    273. Y. Marchalant, F. Cerbai, H. M. Brothers and G. L. Wenk: Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol Aging, 29, 1894-1901 (2008)
    DOI: 10.1016/j.neurobiolaging.2007.04.028

    274. A. Bilkei-Gorzo, O. Albayram, A. Draffehn, K. Michel, A. Piyanova, H. Oppenheimer, M. Dvir-Ginzberg, I. Racz, T. Ulas, S. Imbeault, I. Bab, J. L. Schultze and A. Zimmer: A chronic low dose of (Delta)9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med, advance online publication (2017)
    DOI: 10.1038/nm.4311

    275. J. H. Lee, G. Agacinski, J. H. Williams, G. K. Wilcock, M. M. Esiri, P. T. Francis, P. T. H. Wong, C. P. Chen and M. K. P. Lai: Intact cannabinoid CB1 receptors in the Alzheimer’s disease cortex. Neurochem Int, 57, 985-989 (2010)
    DOI: 10.1016/j.neuint.2010.10.010

    276. M. Solas, P. T. Francis, R. Franco and M. J. Ramirez: CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging, 34(3), 805-808 (2013)
    DOI: 10.1016/j.neurobiolaging.2012.06.005

    277. C. Benito, E. Núñez, R. M. Tolón, E. J. Carrier, A. Rábano, C. J. Hillard and J. Romero: Cannabinoid CB2 Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer’s Disease Brains. J Neurosci, 23 (2003)

    278. E. Núñez, C. Benito, R. M. Tolón, C. J. Hillard, W. S. T. Griffin and J. Romero: Glial expression of cannabinoid CB2 receptors and fatty acid amide hydrolase are beta amyloid–linked events in Down’s syndrome. Neuroscience, 151, 104-110 (2008)
    DOI: 10.1016/j.neuroscience.2007.10.029

    279. R. M. Tolón, E. Núñez, M. R. Pazos, C. Benito, A. I. Castillo, J. A. Martínez-Orgado and J. Romero: The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res, 1283, 148-154 (2009)
    DOI: 10.1016/j.brainres.2009.05.098

    280. Justin R. Piro, Daniel I. Benjamin, James M. Duerr, Y. Pi, C. Gonzales, Kathleen M. Wood, Joel W. Schwartz, Daniel K. Nomura and Tarek A. Samad: A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer’s Disease. Cell Rep, 1(6), 617-623 (2012)
    DOI: 10.1016/j.celrep.2012.05.001

    281. X. Chen, J. Zhang and C. Chen: Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience, 178, 159-168 (2011)
    DOI: 10.1016/j.neuroscience.2011.01.024

    282. C. Stumm, C. Hiebel, R. Hanstein, M. Purrio, H. Nagel, A. Conrad, B. Lutz, C. Behl and A. B. Clement: Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer’s disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition. Neurobiol Aging, 34, 2574-2584 (2013)
    DOI: 10.1016/j.neurobiolaging.2013.05.027

    283. C. Bachmeier, D. Beaulieu-Abdelahad, M. Mullan and D. Paris: Role of the cannabinoid system in the transit of beta-amyloid across the blood–brain barrier. Mol Cell Neurosci, 56, 255-262 (2013)
    DOI: 10.1016/j.mcn.2013.06.004

    284. J. Wu, B. Bie, H. Yang, J. J. Xu, D. L. Brown and M. Naguib: Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging, 34, 791-804 (2013)
    DOI: 10.1016/j.neurobiolaging.2012.06.011

    285. L. M. Eubanks, C. J. Rogers, Beuscher, G. F. Koob, A. J. Olson, T. J. Dickerson and K. D. Janda: A Molecular Link between the Active Component of Marijuana and Alzheimer’s Disease Pathology. Mol Pharm, 3(6), 773-777 (2006)
    DOI: 10.1021/mp060066m

    286. R. Chen, J. Zhang, Y. Wu, D. Wang, G. Feng, Y.-P. Tang, Z. Teng and C. Chen: Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer’s Disease. Cell Rep, 2, 1329-1339 (2012)
    DOI: 10.1016/j.celrep.2012.09.030

    287. A. M. Martín-moreno, D. Reigada, B. G. Ramírez, R. Mechoulam, N. Innamorato, A. Cuadrado, M. L. de Ceballos, G. Ramírez, R. Mechoulam, N. Innamorato, A. Cuadrado and M. L. D. Ceballos: Cannabidiol and Other Cannabinoids Reduce Microglial Activation In vitro and In vivo : Relevance to Alzheimer ’ s Disease. Mol Pharm, 79, 964-973 (2011)
    DOI: 10.1124/mol.111.071290

    288. A. M. Martín-Moreno, B. Brera, C. Spuch, E. Carro, L. García-García, M. Delgado, M. A. Pozo, N. G. Innamorato, A. Cuadrado and M. L. de Ceballos: Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation, 9, 511 (2012)
    DOI: 10.1186/1742-2094-9-8

    289. S. M. B. Asdaq: Antioxidant and hypolipidemic potential of aged garlic extract and its constituent, s-allyl cysteine, in rats. Evid Based Complement Alternat Med, 2015, 328545 (2015)
    DOI: 10.1155/2015/328545

    290. N. B. Chauhan: Effect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576. J Ethnopharmacol, 108(3), 385-94 (2006)
    DOI: 10.1016/j.jep.2006.05.030

    291. A. L. Colin-Gonzalez, S. F. Ali, I. Tunez and A. Santamaria: On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update. Neurochem Int, 89, 83-91 (2015)
    DOI: 10.1016/j.neuint.2015.06.011

    292. H. Javed, M. M. Khan, A. Khan, K. Vaibhav, A. Ahmad, G. Khuwaja, M. E. Ahmed, S. S. Raza, M. Ashafaq, R. Tabassum, M. S. Siddiqui, O. M. El-Agnaf, M. M. Safhi and F. Islam: S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer’s type. Brain Res, 1389, 133-142 (2011)
    DOI: 10.1016/j.brainres.2011.02.072

    293. Z. Qu, V. V. Mossine, J. Cui, G. Y. Sun and Z. Gu: Protective Effects of AGE and Its Components on Neuroinflammation and Neurodegeneration. Neuromolecular Med, 18, 474-482 (2016)
    DOI: 10.1007/s12017-016-8410-1

    294. B. Ray, N. B. Chauhan and D. K. Lahiri: Oxidative insults to neurons and synapse are prevented by aged garlic extract and S-allyl-l-cysteine treatment in the neuronal culture and APP-Tg mouse model. J Neurochem, 117, 388-402 (2011)
    DOI: 10.1111/j.1471-4159.2010.07145.x

    295. T. Imai, Y. Kosuge, H. Saito, T. Uchiyama, T. Wada, S. Shimba, K. Ishige, S. Miyairi, M. Makishima and Y. Ito: Neuroprotective effect of S-allyl-l-cysteine derivatives against endoplasmic reticulum stress-induced cytotoxicity is independent of calpain inhibition. J Pharmacol Sci, 130, 185-188 (2016)
    DOI: 10.1016/j.jphs.2016.03.004

    296. T. Imai, Y. Kosuge, K. Endo-Umeda, H. Miyagishi, K. Ishige, M. Makishima and Y. Ito: Protective effect of S-allyl-l-cysteine against endoplasmic reticulum stress-induced neuronal death is mediated by inhibition of calpain. Amino Acids 46(2), 385-393. (2014)
    DOI: 10.1007/s00726-013-1628-4

    297. F. Calon, G. P. Lim, F. Yang, T. Morihara, B. Teter, O. Ubeda, P. Rostaing, A. Triller, N. Salem, Jr., K. H. Ashe, S. A. Frautschy and G. M. Cole: Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron, 43(5), 633-45 (2004)
    DOI: 10.1016/j.neuron.2004.08.013

    298. M. Lebbadi, C. Julien, A. Phivilay, C. Tremblay, V. Emond, J. X. Kang and F. Calon: Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer’s disease. J Alzheimers Dis, 27, 853-869 (2011)

    299. Y. Zhao, F. Calon, C. Julien, J. W. Winkler, N. A. Petasis, W. J. Lukiw and N. G. Bazan: Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase-and PPARy- Mediated Mechanisms in Alzheimer’s Disease Models. PLoS One, 6 (2011)
    DOI: 10.1371/journal.pone.0015816

    300. E. Hjorth, M. Zhu, V. C. Toro, I. Vedin, J. Palmblad, T. Cederholm, Y. Freund-Levi, G. Faxen-Irving, L. O. Wahlund, H. Basun, M. Eriksdotter and M. Schultzberg: Omega-3 fatty acids enhance phagocytosis of alzheimer’s disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J Alzheimers Dis, 35, 697-713 (2013)

    301. Y. Freund Levi, I. Vedin, T. Cederholm, H. Basun, G. Faxén Irving, M. Eriksdotter, E. Hjorth, M. Schultzberg, B. Vessby, L. O. Wahlund, N. Salem and J. Palmblad: Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer’s disease: The OmegAD study. J Intern Med, 275, 428-436 (2014)
    DOI: 10.1111/joim.12166

    302. M. Burckhardt, M. Herke, T. Wustmann, S. Watzke, G. Langer and A. Fink: Omega-3 fatty acids for the treatment of dementia. In: Cochrane Database of Systematic Reviews. Ed M. Burckhardt. John Wiley & Sons, Ltd, Chichester, UK (2016)
    DOI: 10.1002/14651858.CD009002.pub3

    303. H. N. Yassine, V. Rawat, W. J. Mack, J. F. Quinn, K. Yurko-Mauro, E. Bailey-Hall, P. S. Aisen, H. C. Chui and L. S. Schneider: The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther, 8, 25 (2016)
    DOI: 10.1186/s13195-016-0194-x

    304. M. W. Dysken, M. Sano, S. Asthana, J. E. Vertrees, M. Pallaki, M. Llorente, S. Love, G. D. Schellenberg, J. R. McCarten, J. Malphurs, S. Prieto, P. Chen, D. J. Loreck, G. Trapp, R. S. Bakshi, J. E. Mintzer, J. L. Heidebrink, A. Vidal-Cardona, L. M. Arroyo, A. R. Cruz, S. Zachariah, N. W. Kowall, M. P. Chopra, S. Craft, S. Thielke, C. L. Turvey, C. Woodman, K. A. Monnell, K. Gordon, J. Tomaska, Y. Segal, P. N. Peduzzi and P. D. Guarino: Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA, 311, 33-44 (2014)
    DOI: 10.1001/jama.2013.282834

    305. H. Takatsu, K. Owada, K. Abe, M. Nakano and S. Urano: Effect of vitamin E on learning and memory deficit in aged rats. J Nutr Sci Vitaminol (Tokyo), 55, 389-93 (2009)
    DOI: 10.3177/jnsv.55.389

    306. M. Hashimoto, Y. Tanabe, Y. Fujii, T. Kikuta, H. Shibata and O. Shido: Chronic Administration of Docosahexaenoic Acid Ameliorates the Impairment of Spatial Cognition Learning Ability in Amyloid β–Infused Rats. J Nutr, 135(3), 549-555 (2005)

    307. M. Zimmermann, F. Colciaghi, F. Cattabeni and M. Di Luca: Ginkgo biloba extract: from molecular mechanisms to the treatment of Alzhelmer’s disease. Cell Mol Biol (Noisy-le-grand), 48(6), 613-623 (2002)

    308. V. Conte, K. Uryu, S. Fujimoto, Y. Yao, J. Rokach, L. Longhi, J. Q. Trojanowski, V. M. Lee, T. K. McIntosh and D. Pratico: Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem, 90(3), 758-64 (2004)
    DOI: 10.1111/j.1471-4159.2004.02560.x

    309. D. Cheng, H. Kong, W. Pang, H. Yang, H. Lu, C. Huang and Y. Jiang: B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia. Nutr Neurosci, 19, 461-466 (2016)
    DOI: 10.1179/1476830514Y.0000000136

    310. I. I. Kruman, T. S. Kumaravel, A. Lohani, W. A. Pedersen, R. G. Cutler, Y. Kruman, N. Haughey, J. Lee, M. Evans and M. P. Mattson: Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci, 22, 1752-1762 (2002)

    311. A. Fuso, L. Seminara, R. A. Cavallaro, F. D’Anselmi and S. Scarpa: S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci, 28(1), 195-204 (2005)
    DOI: 10.1016/j.mcn.2004.09.007

    312. A. K. Barbey: Functional Brain Activity Changes after 4 Weeks Supplementation with a Multi-Vitamin / Mineral Combination: A Randomized , Double-Blind , Placebo-Controlled Trial Exploring Functional Magnetic Resonance Imaging and Steady-State Visual Evoked Potentials d. Front Aging Neurosci, 8, 1-20 (2016) doi:10.3.389/fnagi.2016.0.0288
    DOI: 10.3389/fnagi.2016.00288

    313. P. S. Aisen, L. S. Schneider, M. Sano, R. Diaz-Arrastia, C. H. v. Dyck, M. F. Weiner, T. Bottiglieri, S. Jin, K. T. Stokes, R. G. Thomas, L. J. Thal and f. t. A. D. C. Study: High-Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer Disease. JAMA, 300, 1774 (2008)
    DOI: 10.1001/jama.300.15.1774

    314. K. I. Erickson, B. L. Suever, R. S. Prakash, S. J. Colcombe, E. McAuley and A. F. Kramer: Greater intake of vitamins B6 and B12 spares gray matter in healthy elderly: A voxel-based morphometry study. Brain Res, 1199, 20-26 (2008)
    DOI: 10.1016/j.brainres.2008.01.030

    315. L. Flicker, R. N. Martins, J. Thomas, J. Acres, K. Taddei, S. D. Vasikaran, P. Norman, K. Jamrozik and O. P. Almeida: B-vitamins reduce plasma levels of beta amyloid. Neurobiol Aging 29(2), 303-305 (2008)
    DOI: 10.1016/j.neurobiolaging.2006.10.007

    316. C. Cao, J. R. Cirrito, X. Lin, L. Wang, D. K. Verges, A. Dickson, M. Mamcarz, C. Zhang, T. Mori, G. W. Arendash, D. M. Holtzman and H. Potter: Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer’s disease transgenic mice. J Alzheimers Dis, 17(3), 681-97 (2009)
    DOI: 10.3233/JAD-2009-1071

    317. X. Chen, J. W. Gawryluk, J. F. Wagener, O. Ghribi, J. D. Geiger, J. Holash, P. Barberger-Gateau, M. Ancelin and E. Stopa: Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer’s disease. J Neuroinflammation, 5, 12 (2008)
    DOI: 10.1186/1742-2094-5-12

    318. N. Dragicevic, V. Delic, C. Cao, N. Copes, X. Lin, M. Mamcarz, L. Wang, G. W. Arendash and P. C. Bradshaw: Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer’s mice and cells. Neuropharmacology, 63, 1368-1379 (2012)
    DOI: 10.1016/j.neuropharm.2012.08.018

    319. C. Laurent, S. Eddarkaoui, M. Derisbourg, A. Leboucher, D. Demeyer, S. Carrier, M. Schneider, M. Hamdane, C. E. Müller, L. Buée and D. Blum: Beneficial effects of caffeine in a transgenic model of Alzheimer’s disease-like tau pathology. Neurobiol Aging, 35, 2079-2090 (2014)
    DOI: 10.1016/j.neurobiolaging.2014.03.027

    320. J. R. P. Prasanthi, B. Dasari, G. Marwarha, T. Larson, X. Chen, J. D. Geiger and O. Ghribi: Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic Biol Med, 49, 1212-1220 (2010)
    DOI: 10.1016/j.freeradbiomed.2010.07.007

    321. Y.-F. Chu, W.-H. Chang, R. M. Black, J.-R. Liu, P. Sompol, Y. Chen, H. Wei, Q. Zhao and I. H. Cheng: Crude caffeine reduces memory impairment and amyloid β1–42 levels in an Alzheimer’s mouse model. Food Chem, 135, 2095-2102 (2012)
    DOI: 10.1016/j.foodchem.2012.04.148

    322. J. Bednarski, K. Gasińska, T. Straszewski, M. Godek and P. Tutka: Caffeinol: a neuroprotective action in ischemic brain damage. Przegl Lek, 72, 677-81 (2015)

    323. S. Martin-Schild, H. Hallevi, H. Shaltoni, A. D. Barreto, N. R. Gonzales, J. Aronowski, S. I. Savitz and J. C. Grotta: Combined Neuroprotective Modalities Coupled with Thrombolysis in Acute Ischemic Stroke: A Pilot Study of Caffeinol and Mild Hypothermia. J Stroke Cerebrovasc Dis, 18, 86-96 (2009)
    DOI: 10.1016/j.jstrokecerebrovasdis.2008.09.015

    324. X. Zhao, R. Strong, P. Piriyawat, R. Palusinski, J. C. Grotta and J. Aronowski: Caffeinol at the Receptor Level. Stroke, 41(2), 363-367 (2010)
    DOI: 10.1161/STROKEAHA.109.562900

    325. N. T. Aggarwal, J. L. Bienias, D. A. Bennett, R. S. Wilson, M. C. Morris, J. A. Schneider, R. C. Shah and D. A. Evans: The relation of cigarette smoking to incident Alzheimer’s disease in a biracial urban community population. Neuroepidemiology, 26, 140-6 (2006)
    DOI: 10.1159/000091654

    326. T. C. Durazzo, N. Mattsson and M. W. Weiner: Smoking and increased Alzheimer’s disease risk: A review of potential mechanisms. Alzheimers Dement, 10, S122-S145 (2014)
    DOI: 10.1016/j.jalz.2014.04.009

    327. C.-Q. Huang, B.-R. Dong, Y.-L. Zhang, H.-M. Wu and Q.-X. Liu: Association of Cognitive Impairment With Smoking, Alcohol Consumption, Tea Consumption, and Exercise Among Chinese Nonagenarians/Centenarians. Cognitive and Behavioral Neurology, 22, 190-196 (2009)
    DOI: 10.1097/WNN.0b013e3181b2790b

    328. K. A. Alkadhi, K. H. Alzoubi, M. Srivareerat and T. T. Tran: Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of Alzheimer’s disease: prevention by nicotine. Curr Alzheimer Res, 8, 718-31 (2011)
    DOI: 10.2174/156720511797633188

    329. M. Srivareerat, T. T. Tran, S. Salim, A. M. Aleisa and K. A. Alkadhi: Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer’s disease. Neurobiol Aging, 32, 834-844 (2011) doi:10.1.016/j.neurobiolaging.2009.0.4.0.15
    DOI: 10.1016/j.neurobiolaging.2009.04.015

    330. P. Kumar, V. Pillay, Y. E. Choonara, G. Modi, D. Naidoo and L. C. Du Toit: In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy. Int J Mol Sci, 12, 694-724 (2011)
    DOI: 10.3390/ijms12010694

    331. T. Akaishi, T. Morimoto, M. Shibao, S. Watanabe, K. Sakai-Kato, N. Utsunomiya-Tate and K. Abe: Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein. Neurosci Lett, 444, 280-285 (2008)
    DOI: 10.1016/j.neulet.2008.08.052

    332. P. Maher: Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr, 4, 297-307 (2009)
    DOI: 10.1007/s12263-009-0142-5

    333. B. Bayram, B. Ozcelik, S. Grimm, T. Roeder, C. Schrader, I. M. A. Ernst, A. E. Wagner, T. Grune, J. Frank and G. Rimbach: A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation Res, 15, 71-81 (2012)
    DOI: 10.1089/rej.2011.1245

    334. V. Berti, J. Murray, M. Davies, N. Spector, W. H. Tsui, Y. Li, S. Williams, E. Pirraglia, S. Vallabhajosula, P. McHugh, A. Pupi, M. J. de Leon and L. Mosconi: Nutrient patterns and brain biomarkers of Alzheimer’s disease in cognitively normal individuals. J Nutr Health Aging, 19, 413-423 (2015)
    DOI: 10.1007/s12603-014-0534-0

    335. U. Uysal, S. Seremet, J. W. Lamping, J. M. Adams, D. Y. Liu, R. H. Swerdlow and D. J. Aires: Consumption of Polyphenol Plants May Slow Aging and Associated Diseases. Curr Pharm Des, 19, 6094-6111 (2013)
    DOI: 10.2174/1381612811319340004

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Richard E. Hartman, David M. Ross. Effects and mechanisms of actions of phytochemicals on Alzheimer’s disease neuropathology. Frontiers in Bioscience-Elite. 2018. 10(2); 300-333.