Dysregulation of brain insulin signaling: A mechanistic link between diabetes and Alzheimer's disease

Abstract

Brain glucose uptake and utilization are impaired in Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM), which is characterized by deficient glucose uptake and utilization in the periphery due to insulin resistance, increases the risk for AD, but the underlying mechanism linking T2DM and AD is not understood. This study was aimed to understand whether brain insulin resistance is the link between T2DM and AD, which could contribute to AD via down-regulation of insulin-PI3K-AKT signaling. Autopsied frontal cortices from 9 AD, 10 T2DM, 8 T2DM-AD and 7 control cases were included in this study. All the groups had similar postmortem intervals (2.7 ± 0.6 hours) and ages (82.3 ± 4.9 years), The levels of the various components of the insulin-PI3K-AKT signaling pathway [including insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β)], total tau, phosphorylated tau, and calpain I were determined by quantitative Western blots. The activities of the insulin-PI3K-AKT signaling components were estimated by measuring the levels of the active/phosphorylated forms of the proteins. We found down-regulation of both the levels and activities of several components of the insulin-PI3K-AKT signaling pathway in the postmortem brains from individuals with T2DM or with AD. The deficiency of insulin-PI3K-AKT signaling was more severe in those individuals suffering from both T2DM and AD. The down-regulation of insulin-PI3K-AKT signaling was accompanied by activation of GSK-3β, the major tau kinase in the brain. The levels and the activation of the insulin-PI3K-AKT signaling components were correlated negatively with the level of tau phosphorylation at several abnormal phosphorylation sites and with the activation of calpain I in the brain. Our results suggest that the down-regulation of insulin-PI3K-AKT signaling, which appeared to be caused by calpain over-activation, might be the mechanistic link between T2DM and AD. Brain insulin resistance in T2DM may increase the risk for AD by decreased insulin-PI3K-AKT signaling and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration.