Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease

Abstract

Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aβ accumulation. High-fat diet enhanced glucose intolerance, brain soluble Aβ, and memory impairment in 3xTg-AD mice. Strikingly, a single insulin injection reversed the deleterious effects of HFD on memory and soluble Aβ levels, partly through changes in Aβ production and/or clearance. Our results are consistent with the development of a vicious cycle between AD and diabetes, potentiating both peripheral metabolic disorders and AD neuropathology. The capacity of insulin to rapidly break the deleterious effects of this cycle on soluble Aβ concentrations and memory has important therapeutic implications.