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Asp664 cleavage of amyloid precursor protein induces tau phosphorylation by decreasing protein phosphatase 2A activity.
MedLine Citation:
PMID:  23020770     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Caspase cleavage of amyloid precursor protein (APP) has been reported to be important in Aβ-mediated neurotoxicity. However, the underlying mechanisms are not clearly understood. In this study, we explored the effect of caspase cleavage of APP on tau phosphorylation in relation to Aβ. We found that Asp664 cleavage of APP increased tau phosphorylation at Thr212 and Ser262 in N2A cells and primary cultured hippocampal neurons. Compared to wild-type APP, PP2A activity was significantly increased when Asp664 cleavage was blocked by the D664A point mutation. Furthermore, we found that overexpression of C31 reduced PP2A activity. C31 binds directly to the PP2A catalytic subunit, through the NPTY motif, which is essential for C31-induced tau hyperphosphorylation. However, it appears that the other fragment produced by Asp664 cleavage, Jcasp, modulates neither PP2A activity nor tau hyperphosphorylation. Asp664 cleavage and accompanying tau hyperphosphorylation were remarkably diminished by blockage of Aβ production using a γ-secretase inhibitor. Taken together, our results suggest that Asp664 cleavage of APP leads to tau hyperphosphorylation at specific epitopes by modulating PP2A activity as a downstream of Aβ. Direct binding of C31 to PP2A through the C31-NPTY domain was identified as a mechanism underlying this effect. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Authors:
Seok Soon Park; Hyun-Jung Jung; Yoon-Jeong Kim; Tae Kwan Park; Chaeyoung Kim; Heesun Choi; In Hee Mook-Jung; Edward H Koo; Sun Ah Park
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-29
Journal Detail:
Title:  Journal of neurochemistry     Volume:  -     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Affiliation:
Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
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