期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 23, 期 4, 页码 617-627出版社
IOS PRESS
DOI: 10.3233/JAD-2010-100987
关键词
Alzheimer's disease; calpain; hyperphosphorylation; protein phosphatase 2B; tau
资金
- Nantong University
- New York State Office for people with Developmental Disabilities
- National Natural Science Foundation of China [30770468, 30973143]
- Natural Science Foundation of Jiangsu Province, China [BK2009159]
- US National Institutes of Health [AG027429, AG019158]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- NATIONAL INSTITUTE ON AGING [R01AG019158, P30AG019610, R01AG027429] Funding Source: NIH RePORTER
Protein phosphatase 2B (PP2B) is one of the major brain phosphatases and can dephosphorylate tau at several phosphorylation sites in vitro. Previous studies that measured PP2B activity in human brain crude extracts showed that PP2B activity was either unchanged or decreased in Alzheimer's disease (AD) brain. These results led to the speculation that PP2B might regulate tau phosphorylation and that a down-regulation of PP2B might contribute to abnormal hyperphosphorylation of tau. In this study, we immunoprecipitated PP2B from brains of six AD subjects and seven postmortem-and age-matched controls and then measured the phosphatase activity. We found a three-fold increase in PP2B activity in AD brain as compared with control brains. The activation was due to the partial cleavage of PP2B by calpain I that was activated in AD brain. The truncation of PP2B appeared to alter its intracellular distribution in the brain. In human brains, PP2B activity correlated positively, rather than negatively, to the levels of tau phosphorylation at several sites that can be dephosphorylated by PP2B in vitro. Truncation of PP2B in the frontal cortex was more than in the temporal cortex, and tau phosphorylation was also more in the frontal cortex. Taken together, these results indicate that truncation of PP2B by calpain I elevates its activity but does not counteract the abnormal hyperphosphorylation of tau in AD brain.
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