期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 16, 期 1, 页码 149-156出版社
IOS PRESS
DOI: 10.3233/JAD-2009-0933
关键词
Alzheimer's disease; amyloid-beta; cdk5; Fyn; lipid rafts; neuronal membrane; tau phosphorylation
资金
- Fondecyt [1050198, 1080254]
- International Center for Biomedicine
- Millennium Institute CBB project
- Conicyt fellowship
- National Institutes of Health [NS32100]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS032100] Funding Source: NIH RePORTER
Alzheimer's disease (AD) is characterized by the accumulation of protein filaments, namely extracellular amyloid-beta (A beta) fibrils and intracellular neurofibrillary tangles, which are composed of aggregated hyperphosphorylated tau. Tau hyperphosphorylation is the product of deregulated Ser/Thr kinases such as cdk5 and GSK3 beta. In addition, tau hyperphosphorylation also occurs at Tyr residues. To find a link between A beta and tau phosphorylation, we investigated the effects of short-term A beta treatments on SHSY-5Y cells. We analyzed phosphorylated tau variants in lipid rafts and the possible role of Tyr18 and Ser396/404 tau phosphorylation in A beta-induced signaling cascades. After 2 min of A beta treatment, phospho-Tyr18-tau and its association with rafts increased. Phospho-Ser 396/404-tau became detectable in rafts after 10 min treatment, which temporally correlated with the detection of cdk5 and p35 activator in lipid rafts. To determine the role of cdk5 in tau phosphorylation at Ser396/404 in lipid rafts, we pre-incubated cells with cdk5 inhibitor roscovitine, and observed that the A beta-induced tau phosphorylation at Ser 396/404 in rafts was abolished as well as cdk5/p35 association with rafts. These data suggest a role for cdk5 in the A beta-promoted early events involving tau hyperphosphorylation, and their possible implications for AD pathogenesis.
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