Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes.
J Pathol
; 225(1): 54-62, 2011 Sep.
Article
em En
| MEDLINE
| ID: mdl-21598254
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-3ß, 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
/
Diabetes Mellitus Tipo 2
/
Doença de Alzheimer
/
Insulina
Tipo de estudo:
Etiology_studies
Limite:
Aged
/
Aged80
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Pathol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos