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.

Brain metabolic dysfunction at the core of Alzheimer's disease

“…Insulin accelerates trafficking of AβPP-Aβ from the trans-Golgi network to the plasma membrane and its extracellular secretion [53], and also inhibits its intracellular degradation by insulin-degrading enzyme [54]. In hyper-insulin states, IDE can be diverted to degrade insulin, and thereby allow AβPP-Aβ to accumulate [55]. Most important, impaired insulin signaling can disrupt processing of AβPP and clearance of AβPP-Aβ [56].…”

“…Insulin and IGF resistance increase with aging, while longevity is associated with preservation of insulin/IGF responsiveness [55,96,97]. However, cumulative challenges and stresses over a lifespan can damage cells and tissues due to excessive signaling through insulin/IGF-1 receptors [98,99].…”

Insulin deficiency: A possible link between obesity and cognitive function

“…Previous reports demonstrated a clear correlation between blood and CNS insulin concentrations (Banks et al, 1997). Defective transport system of insulin from BBB in obesity is responsible for scarce amount of insulin in the brain (Heni et al, 2014) and obese individuals with insulin resistance are at higher risk of neurodegenerative diseases (Schuh et al, 2011). It seems that whole body insulin has a central role in regulating the brain insulin action and obesity leads to disturbed insulin sensitivity and delayed entrance of insulin into brain via BBB (Heni et al, 2014).…”

Relationships Between Diabetes and Cognitive Impairment

“…73–75 Furthermore, evidence suggests that chronic stress over a lifespan damages cells because of excessive signaling through insulin/IGF-1 receptors. 76 Correspondingly, neuronal overexpression of IRS2 leads to increased fat mass, insulin resistance, and glucose intolerance with aging.…”