Insulin, Cholesterol and A-beta: Roles and Mechanisms in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) and tau pathologies, insulin resistance, neuro-inflammation and dysregulation of cholesterol homeostasis, all of which play a role in neuro-degeneration. The main aim of this study was to determine possible relationships between insulin signaling, cholesterol biosynthesis and their effects on Aβ, and inflammatory response in vitro. Insulin treatment increased cholesterol synthesis in human Neuroblastoma SH-SY5Y (SHY) and mouse neuroblastoma 2a (N2a) and N2a transfected with human APP (N2a-APP) by up-regulating biosynthesis enzymes including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3methyl-glutaryl-CoA reductase (HMGCR) through sterol regulatory element binding protein-2 (SREBP2) up-regulation. Aβ caused insulin resistance in N2a-APP cells by phosphorylating IRS-1 at Ser612, inhibiting signaling to downstream targets. Aβ1-42-treated SHY exhibited similar IRS-1 phosphorylation at Ser612 and inflammatory response of JNK activation. Aβ1-42 caused down-regulation of neuro-protective/anti-inflammatory DHCR24, and an increase in HMGCR levels indicating dysregulation of cholesterol homeostasis in SHY cells. Insulin resistance, Aβ toxicity, neuro-inflammation and dysregulation of cholesterol homeostasis appear to be intertwined processes in AD that should be studied simultaneously.