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[O2–03–01]: PROTEIN CO‐EXPRESSION NETWORK ANALYSIS IN ASYMPTOMATIC AND SYMPTOMATIC ALZHEIMER'S DISEASE
Author(s) -
Seyfried Nicholas T.,
Dammer Eric B.,
Duong Duc M.,
Deng Qiudong,
Troncoso Juan C.,
Thambisetty Madhav,
Lah James J.,
Levey Allan I.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.155
Subject(s) - pathogenesis , pathological , dementia , disease , proteome , asymptomatic , neuroscience , alzheimer's disease , pathology , psychology , medicine , biology , bioinformatics
the activity. In AD brain, GSK-3b is truncated at the C-terminus by over-activated calpain I, leading to an increase in its activity. However, the effect of truncation on its phosphorylation is unknown.Methods:We determined themolecular mechanism bywhich the truncation of GSK3b leads to increase in its activity by usingWestern blots, immunofluorescencent staining, subcellular fractionation, in vitro dephosphorylation, and co-immunoprecipitation. Results:We found that in AD brain and in cultured cells, theC-terminally truncatedGSK-3bwas less phosphorylated at Ser9 than the full-length enzyme. The truncated GSK-3b was observed more than the full-length in the nucleus in cultured cells and in AD brain. The truncated GSK-3b interacted with protein phosphatase 2A (PP2A) more strongly and was dephosphorylated by PP2A more efficiently than the full-lengthGSK-3b.Conclusions:TheC-terminal truncation of GSK-3b promotes its nuclear translocation and enhances its interaction with and dephosphorylation by PP2A. Thus, the truncation of GSK-3b may enhance its activity through Ser9 dephosphorylation by PP2A. These findings shed a new light onto the role of calpain-GSK-3b-PP2A in tau pathogenesis in AD.