The interrelationship between insulin resistane and Alzheimer development

Abstract

Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence on the synthesis and degradation of A β and as a consequence of the cascade of neuronal alterations resulting from the effects of danger/alarm signals from oligomeric amyloid species. Additionally, recent studies have indicated that certain signal transduction pathways downstream of the InsR may also promote the generation of A β peptides by modulating the cleavage of the parent A β precursor protein (A β PP) at the γ -secretase site, a cleavage site necessary for A β amyloidogenicity. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (C SF) concentration. Peripheral hyperinsulinemia cor relates with an abnormal removal of the amyloid beta peptide (A β ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3 β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and reduced insulin signaling in brain, altering all of insulin’s actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD.