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

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	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
	Liu, SJ ; Zhang, AH ; Li, HL ; Wang, Q ; Deng, HM ; Netzer, WJ ; Xu, HX ; Wang, JZ ; Xu HX(许华曦)
刊名	http://dx.doi.org/10.1046/j.1471-4159.2003.02070.x
	2003-12
关键词	PAIRED HELICAL FILAMENTS ALZHEIMERS-DISEASE BRAIN NANOELECTROSPRAY MASS-SPECTROMETRY AMYLOID PRECURSOR PROTEIN ABNORMAL PHOSPHORYLATION NEUROFIBRILLARY TANGLES DIABETES-MELLITUS TRANSGENIC MICE MICROTUBULES GSK-3
英文摘要	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.
语种	英语
出版者	J NEUROCHEM
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/93384]
专题	医学院－已发表论文
推荐引用方式 GB/T 7714	Liu, SJ,Zhang, AH,Li, HL,et al. 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[J]. http://dx.doi.org/10.1046/j.1471-4159.2003.02070.x,2003.
APA	Liu, SJ.,Zhang, AH.,Li, HL.,Wang, Q.,Deng, HM.,...&许华曦.(2003).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.http://dx.doi.org/10.1046/j.1471-4159.2003.02070.x.
MLA	Liu, SJ,et al."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".http://dx.doi.org/10.1046/j.1471-4159.2003.02070.x (2003).