Molecular Pathophysiology of Insulin Depletion, Mitochondrial Dysfunction, and Oxidative Stress in Alzheimer's Disease Brain.

Accumulating clinical data indicates that insulin resistance and diabetes mellitus (DM) are major risk factors for Alzheimer's disease (AD); however, the exact mechanisms on how insulin resistance and DM act as risk factors for AD remain unclear. Recent progress in gene expression profiling of AD brains revealed that brain insulin production and insulin signaling are significantly impaired, indicating that AD brain exhibits a feature of brain diabetes with depletion of brain insulin, which causes mitochondrial dysfunction with increased oxidative stress, thereby increasing sensitivity to peripheral diabetes. Such diabetic condition in early stage of AD brain can be exacerbated by peripheral diabetes, namely, through hyperglycemia, hyperinsulinemia, or impaired insulin response. In this chapter, I reviewed mitochondrial dysfunction and oxidative stress in AD brain and discussed how those events are involved in AD pathogenesis.