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- Title
Effects of endogenous β-amyloid overproduction on tau phosphorylation in cell culture.
- Authors
Ze-Fen Wang; Hong-Lian Li; Xia-Chun Li; Qi Zhang; Qing Tian; Qun Wang; Huaxi Xu; Jian-Zhi Wang
- Abstract
Alzheimer's disease is characterized by β-amyloid (Aβ) overproduction and tau hyperphosphorylation. Recent studies have shown that synthetic Aβ promotes tau phosphorylation in vitro. However, whether endogenously overproduced Aβ promotes tau phosphorylation and the underlying mechanisms remain unknown. Here, we used mouse neuroblastoma N2a stably expressing wild-type amyloid precursor protein (APPwt) or the Swedish mutant APP (APPswe) to determine the alterations of phosphorylated tau and the related protein kinases. We found that phosphorylation of tau at paired helical filament (PHF)-1, pSer396 and pThr231 epitopes was significantly increased in cells transfected with APPwt and APPswe, which produced higher levels of Aβ than cells transfected with vector or amyloid precursor-like protein 1. The activity of glycogen synthase kinase-3 (GSK-3) was up-regulated with a concomitant reduction in the inhibitory phosphorylation of GSK-3 at its N-terminal Ser9 residue. In contrast, the activity of cyclin-dependent kinase-5 (CDK-5) and protein kinase C (PKC) was down-regulated. Inhibition of GSK-3 by LiCl, but not inhibition of CDK-5 by roscovitine, arrested Aβ secretion and tau phosphorylation. Inhibition of PKC by GF-109203X activated GSK-3, whereas activation of PKC by phorbol-12,13-dibutyrate inhibited GSK-3. These results suggest that endogenously overproduced Aβ induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation.
- Subjects
ALZHEIMER'S disease; AMYLOID beta-protein; PHOSPHORYLATION; CELL culture; CYCLIN-dependent kinases; GLYCOGEN synthase kinase-3; PROTEIN kinase C
- Publication
Journal of Neurochemistry, 2006, Vol 98, Issue 4, p1167
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2006.03956.x