title: Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer's disease.
abstract: 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 tau in AD brain.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yin
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.forename: Jianlan
authors.initials: J
authors.lastname: Gu
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins; D019703:Calcineurin