Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory

被引:229
作者
Liu, SJ
Zhang, AH
Li, HL
Wang, Q
Deng, HM
Netzer, WJ
Xu, HX
Wang, JZ [1 ]
机构
[1] HUST, Tongji Med Coll, Dept Pathophysiol, Inst Neurosci, Wuhan, Peoples R China
[2] Rockefeller Univ, Fisher Ctr Res Alzheimers Dis, New York, NY 10021 USA
[3] Burnham Inst, Ctr Neurosci & Aging, La Jolla, CA 92037 USA
[4] Xiamen Univ, Sch Life Sci, Xiamen, Peoples R China
关键词
Alzheimer's disease; glycogen synthase kinase-3; protein kinase C; phosphoinositol-3; kinase; spatial memory;
D O I
10.1046/j.1471-4159.2003.02070.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
引用
收藏
页码:1333 / 1344
页数:12
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