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Caspase cleavage of amyloid precursor protein (APP) has been reported to be important in amyloid beta protein (Ab)-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 Ab. We found that Asp664 cleavage of APP increased tau phosphorylation at Thr212 and Ser262 in N2A cells and primary cultured hippocampal neurons. Compared with wild-type APP, protein phosphatase 2A (PP2A) activity was significantly increased when Asp664 cleavage was blocked by the D664A point mutation. Furthermore, we found that over-expression of C31 reduced PP2A activity. C31 binds directly to the PP2A catalytic subunit, through the asparagine, proline, threonine, tyrosine (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 Ab production using a c-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 Ab. Direct binding of C31 to PP2A through the C31-NPTY domain was identified as a mechanism underlying this effect. Keywords: amyloid precursor protein, caspase, phosphorylation, protein phosphatase 2, tau. J. Neurochem. (2012) 123, 856-865. Amyloid plaques, which consist of amyloid beta protein (Ab) and neurofibrillary tangles composed of hyperphosphorylated tau are the hallmarks of Alzheimer's disease (AD). The interaction between these two major pathogenic proteins contributes synergistically to AD progression. The exposure of tau to Ab accelerates tau pathology, such as hyperphosphorylation (De Felice et al. 2008;Ryan et al. 2009) and mislocalization into dendritic spines, leading to a loss of spines and degeneration of dendrites (Zempel et al. 2010). In addition, Ab accelerates the spatiotemporal progression of tau pathology, as demonstrated in an AD mouse model (Hurtado et al. 2010). Numerous studies have shown that tau is a downstream mediator of Ab. However, the mechanism through which Ab induces tau pathology is not understood.Received August 16, 2012; accepted September 23, 2012. Address correspondence and reprint requests to Sun Ah Park, Associate professor of Neurology, Soonchunhyang University Bucheon Hospital, 1174, Jung-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Republic of Korea 420-767. E-mail: sapark@schmc.ac.kr 1 The first two authors equally contributed to this study.Abbreviation used: A, alanine; AD, Alzheimer's disease; APP, amyloid precursor protein; Asp, aspartic acid; Ab, amyloid beta protein; cdk5, cell division protein kinase 5; DAPI, 4′,6-diamidino-2-phenylindole; DAPT,]-S-phenylglycine t-butyl ester; D, aspartic acid; ERK, extracellular signal-regulated kinases; GFP, green fluorescence p...

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