O4‐02–05: Molecular mechanism by which type 2 diabetes mellitus increases the risk for Alzheimer's disease
Year: 2008
Type: article
Abstract: Brain glucose uptake/metabolism is impaired in Alzheimer disease (AD), but the cause leading to this impairment and its role in the disease mechanism are not understood. Glucose uptake into the neuron from blood stream is mediated by glucose transporters (GLUT). We studied the four major brain GLUTs (GLUT1–4) in AD and type 2 diabetes mellitus (DM-2) by quantitative Western blots. DM-2 is believed to be a risk factor for AD and is characterized by glucose metabolism impairment. We found that levels of GLUT1 and GLUT3, the two major GLUTs responsible for glucose uptake into neurons, were decreased in AD brain. This decrease correlated to the decrease in protein O-GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. Furthermore, expression of hypoxia-inducible factor 1, a major regulator of GLUT1 and GLUT3 expression, was down-regulated in AD brain. In DM-II brain, we found a decrease in the level of GLUT3, but not of GLUT1, as compared to the control brains. The decrease in GLUT3 was accompanied by decreased protein O-GlcNAcylation and by tau hyperphosphorylation at some abnormal hyperphosphorylation sites in DM-II brains. These studies provide a possible mechanism by which GLUT deficiency could cause impaired brain glucose uptake/metabolism and contribute to neurodegeneration via down-regulation of O-GlcNAcylation and hyperphosphorylation of tau in AD. These findings also suggest that DM-II could increase the risk for AD by the same mechanism.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2007024588