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.

Response to Comment on Vandal et al. Insulin Reverses the High-Fat Diet–Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease. Diabetes 2014;63:4291–4301

“…Ghanim and Dandona for their comments (1) on our article (2). Their results showing that insulin infusion leads to decreased expression of amyloid precursor protein (APP) and presenilins in human monocytes (3) are in line with reports in cell culture (4) and support the use of insulin in Alzheimer disease (AD) (5).…”

“…The other key mechanism by which cerebral Ab concentrations are regulated is through brainblood clearance. Indeed, we found a coinciding increase in plasma Ab concentrations minutes after the systemic insulin administration (2). Although data directly confirming that insulin triggers a rapid Ab efflux via the blood-brain barrier are still lacking, higher cerebral blood flow (7) and cerebrospinal fluid Ab levels (8) have been reported 30 and 120 min after the administration of insulin, respectively.…”

[P4–134]: Insulin Resistance Is Associated With Reductions in Specific Cognitive Domains and Increases in CSF Tau in Cognitively Normal Adults

“…Numerous studies in various animal models have shown that diet (HF diet/sucrose/fructose) or chemical (administration of the β-cell toxin streptozotocin (STZ)) induced diabetes promote, tau phosphorylation, and synaptic/neurodegeneration 23,[43][44][45][46][47] . The potential mechanisms may involve neuroinflammatory and oxidative stress mechanisms 14 .…”

“…22). Further, recent evidence indicates β-cell dysfunction in AD rodent models 23,24 and that Aβ and Tau have been shown to accumulate in human post-mortem pancreatic tissue in T2D 25 , possibly contributing to β-cell dysfunction. Despite this evidence, there is a lack of literature investigating pancreatic β-cell activity (HOMA-B) on cognition and AD related pathology.…”

Comment on Vandal et al. Insulin Reverses the High-Fat Diet–Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease. Diabetes 2014;63:4291–4301

“…In a recent issue of Diabetes, Vandal et al (1) showed that the administration of a high-fat diet induced the deposition of b-amyloid in the brains of mice. They also showed that the deposition of amyloid was prevented or reversed by the administration of insulin.…”