Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Abstract

Brain glucose metabolism is impaired in Alzheimer’s disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin–PI3K–AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM–AD and seven control cases. We found decreases in the levels and activities of several components of the insulin–PI3K–AKT signalling pathway in AD and T2DM cases. The deficiency of insulin–PI3K–AKT signalling was more severe in individuals with both T2DM and AD (T2DM–AD). This decrease in insulin–PI3K–AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin–PI3K–AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin–PI3K–AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin–PI3K–AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer’s disease.

An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia

“…The level of PI3K-AKT signaling was negatively correlated with tau phosphorylation [96]. In addition, both neuronal membrane glucose transporter 3 and GlcNAcylation levels of tau were decreased in the brain of T2DM patients due to an increased tau phosphorylation [97].…”

“…At molecular and cellular level, the deficiency of insulin-PI3K-AKT signaling was more severe in individuals with both T2DM and AD than in those with either one alone [96].…”

Insulin Receptor Signaling in Cones

“…The phosphorylation status in Nrl Ϫ/Ϫ mouse retina was set at 100%. deficient brain insulin signaling pathway in Alzheimer disease and diabetes has recently been reported (75,76).…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…38,39 There have been many post-mortem brain studies showing decreases in key insulin signaling proteins in the brains of people with AD. [40][41][42][43] In addition, Talbot et al 44 showed an impaired response to insulin in post-mortem brain regions including the cerebellar cortex and hippocampal formation compared to healthy controls who did not have evidence of insulin resistance at peripheral tissues. 44 This study was critical to show a functional impairment in response to insulin in the CNS, but not necessarily the peripheral tissues, in people with cognitive impairment.…”