Molecular basis of diabetes as a risk for Alzheimer's disease

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by peripheral insulin resistance. Epidemiological studies have revealed that T2DM increases the risk for Alzheimer disease (AD), but the underlying mechanism is unknown. We found that in brains of individuals with T2DM or AD, insulin signaling and glucose transporters, which are crucial to glucose transport from blood into the neuron, were dysregulated. These abnormalities can lead to decreased glucose uptake/metabolism in the brain. Deficient glucose uptake/metabolism in cultured cells induced by glucose deprivation or in rodents induced by fasting caused decreased protein O-GlcNAcylation (a unique type of O-glycosylation of protein with Beta-N-acetyl-glucosamine, GlcNAc) and abnormal hyperphosphorylation of tau. In cell cultures and in metabolically active rat brain slices, elevation of O-GlcNAcylation induced decreased phosphorylation of tau at multiple phosphorylation sites, whereas reduction of O-GlcNAcylation resulted in hyperphosphorylation of tau. Decreased O-GlcNAcylation, hyperphosphorylation of tau, and up-regulation of glycogen synthase kinase-3Beta (GSK-3Beta) were also observed in T2DM brain and in AD brain. Taken together, our findings provide a molecular basis of T2DM to be a risk for AD. We propose that the down-regulation of insulin signaling and glucose uptake/mechanism in the brain could promote abnormal hyperphosphorylation of tau and consequently neurodegeneration via (1) an over-activation of GSK-3? (a major tau kinase) and (2) a decrease in tau O-GlcNAcylation. These common abnormalities in both T2DM and AD brains could facilitate neurodegeneration and explain why T2DM increases the risk for AD.