Open Access
Review

Therapeutic targets of brain insulin resistance in sporadic Alzheimer’s disease

Suzanne M. de la Monte1,*
1
Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI
DOI: 10.2741/482 Volume 4 Issue 4, pp.1582-1605
Published: 01 January 2012
(This article belongs to the Special Issue Alzheimer's disease)
*Corresponding Author(s):  
Suzanne M. de la Monte
E-mail:  
Suzanne_DeLaMonte_MD@Brown.edu
Abstract

Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to ADassociated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.

Key words

Amyloid, Anti-oxidants, Brain diabetes, Brain insulin resistance, Incretins, Insulin, Insulin sensitizers, Liver-Brain-Axis, Metal Chelation, Neuroprotection, Nitrosamine, Oxidative Stress, Polyphenols, Statins, Streptozotocin, Tau, Type 3 diabetes

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Suzanne M. de la Monte. Therapeutic targets of brain insulin resistance in sporadic Alzheimer’s disease. Frontiers in Bioscience-Elite. 2012. 4(4); 1582-1605.