Mechanisms of brain aging regulation by insulin: implications for neurodegeneration in late-onset Alzheimer's disease

Abstract

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes-both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation.

Figure 1

Key components of the Metabolic Syndrome (Met.S), and their possible mechanisms leading to neurodegeneration and cognitive decline. All Met.S components may contribute to cause cerebral small-vessel disease, neurodegeneration, and cognitive decline. However, obesity-related insulin resistance, causing hyperinsulinism, is thought to be the unifying pathophysiological mechanism for the development of Met.S. Aging is associated with increased insulin resistance and Met.S prevalence, and may also aggravate the severity/control of most components of this syndrome. Adapted, with authorization, from Roriz-Filho et al. 2009 [27].