Abstract

Although increased lifespan is associated with reduced insulin signaling, insulin signaling is essential for neuronal development and survival. Insulin resistance is central to Type II diabetes and is also implicated in the pathogenesis of Alzheimer’s Disease (AD). This has prompted ongoing clinical trials in AD patients to test the efficacy of improving insulin – like signaling with dietary ω-3 fatty acids or insulin – sensitizing drugs as well as exercise regimens. Here we review the role of insulin signaling in brain aging and AD, concluding that the signaling pathways downstream to neurotrophic and insulin signaling are defective and coincident with aberrant phosphorylation and translocation of key components, notably AKT and GSK3β, but also rac> PAK signaling. These responses are likely to contribute to defects in synaptic plasticity, learning and memory. Both oligomers of β-amyloid (which are elevated in the AD brain) and pro-inflammatory cytokines (which are elevated in the aged or AD brain) can be used to mimic the trophic factor/insulin resistance observed in AD, but details on other factors and mechanisms contributing to this resistance remain elusive. A better understanding of the precise mechanisms underlying alterations in the insulin/neurotrophic factor signal transduction pathways should aid the search for better AD therapeutic and prevention strategies.

Keywords: Insulin resistance; TZDs (thiazolidinediones); Brain aging

Article Outline

1. Introduction

2. Insulin signaling

3. Insulin signaling in the brain

4. Alzheimer’s Disease (AD)

5. Insulin signaling and AD

5.1. Diabetes

5.2. Insulin and trophic factor levels in AD

5.3. IGF-1

5.4. Regulation of insulin degrading enzyme (IDE) and Aβ clearance

5.5. Aβ oligomer-induced dendritic spine protein loss and PAK kinases

5.6. PAK and drebrin protection by insulin signaling

5.7. Oxidative damage and inflammation

5.8. Aberrant downstream insulin signaling in AD

5.9. Insulin resistance and AD

6. Possible causes of insulin resistance relevant to AD

6.1. Amyloid peptides

6.2. Inflammation

6.3. Obesity, Type II diabetes and brain aging

7. Clinical approaches

7.1. Insulin

7.2. Insulin-sensitizers – TZDs

7.3. Exercise

7.4. ω-3 (n − 3) fatty acids

7.5. Small molecule insulin and trophic factor mimetics

7.6. Conclusion

Acknowledgements

Glossary

References