J Clin Neurol.  2011 Mar;7(1):10-18. 10.3988/jcn.2011.7.1.10.

A Common Pathogenic Mechanism Linking Type-2 Diabetes and Alzheimer's Disease: Evidence from Animal Models

• Park SA

• KMID: 1452567
• DOI: http://doi.org/10.3988/jcn.2011.7.1.10

Abstract

The failure of large-scale drug trials targeting the amyloidogenic pathway in Alzheimer's disease (AD) is increasing the need to identify a novel pathogenic mechanism. Studies finding a relationship between sporadic AD and type-2 diabetes mellitus (T2DM) are now receiving more attention. The risk for developing both T2DM and sporadic AD increases exponentially with age, and having T2DM doubles the risk of developing AD. The postmortem brains of AD patients show altered activities of insulin receptors and downstream molecules, as well as reduced protein and mRNA levels of insulin. More-recent laboratory research using animal models has identified mechanisms that are shared by diabetes and AD. Exogenous application of streptozotocin, which disrupts systemic insulin secretion, results in insulin deficiency, increased tau phosphorylation, and cognitive impairments that can be reversed by exogenous insulin supplementation. However, AD pathology is more severe in T2DM animal models exhibiting hyperinsulinemia and insulin resistance, and this is not modulated by insulin. The symptoms of this AD pathology included increased tau phosphorylation at multiple sites, increased tau cleavage, and greater neuronal and synaptic damage, even with increased amyloid beta protein production. It has therefore been suggested that hyperinsulinemia and insulin resistance represent major factors underlying AD in T2DM. A recent study involving cross-mating ob/ob and amyloid precursor protein transgenic mice provided evidence that T2DM and AD aggravate each other, and suggested that cerebral vessels constitute an important substrate that is commonly damaged by the two major disorders. Given the evidence provided by animal models, further investigation of the mechanisms underlying T2DM in AD should help to identify potential treatment targets in AD.

Keyword

Alzheimer's disease; animal model; diabetes; insulin resistance; mechanism

MeSH Terms

Alzheimer Disease
Amyloid
Amyloid beta-Peptides
Animals
Brain
Diabetes Mellitus
Humans
Hyperinsulinism
Insulin
Insulin Resistance
Mice
Mice, Transgenic
Models, Animal
Neurons
Phosphorylation
Receptor, Insulin
RNA, Messenger
Streptozocin
Amyloid
Amyloid beta-Peptides
Insulin
RNA, Messenger
Receptor, Insulin
Streptozocin

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