期刊
JOURNAL OF PATHOLOGY
卷 225, 期 1, 页码 54-62出版社
WILEY
DOI: 10.1002/path.2912
关键词
Alzheimer's disease; diabetes; insulin; PI3K; AKT; GSK-3 beta; calpain; beta-arrestin-2
资金
- National Institute on Ageing (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- New York State Office for People with Developmental Disabilities
- US National Institutes of Health [R01 AG027429, R03 TW008123, R01 AG031969, R01 AG019158]
- US Alzheimer's Association [IIRG-10-170405]
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-3 beta, 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. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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