Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer's disease

被引:83
作者
Chu, J. [1 ]
Lauretti, E. [1 ]
Pratico, D. [1 ]
机构
[1] Temple Univ, Dept Pharmacol, Sch Med, Ctr Translat Med, 3500 North Broad St,947 MERB, Philadelphia, PA 19140 USA
关键词
AMYLOID PRECURSOR PROTEIN; CASPASE ACTIVATION; MOUSE MODEL; HIPPOCAMPAL-NEURONS; CELL-DEATH; INHIBITION; SURVIVAL; 5-LIPOXYGENASE; RECEPTOR; MEMORY;
D O I
10.1038/mp.2016.214
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
The pathological hallmark of Alzheimer's disease (AD) is accumulation of misfolded amyloid-beta peptides and hyperphosphorylated tau protein in the brain. Increasing evidence suggests that serine-aspartyl proteases-caspases are activated in the AD brain. Previous studies identified a caspase-3 cleavage site within the amyloid-beta precursor protein, and a caspase-3 cleavage of tau as the mechanisms involved in the development of A beta and tau neuropathology, respectively. However, the potential role that caspase-3 could have on tau metabolism remains unknown. In the current studies, we provide experimental evidence that caspase-3 directly and specifically regulates tau phosphorylation, and demonstrate that this effect is mediated by the GSK3 beta kinase pathway via a caspase-3-dependent cleavage of the protein kinase B (also known as Akt). In addition, we confirm these results in vivo by using a transgenic mouse model of AD. Collectively, our findings demonstrate a new role for caspase-3 in the neurobiology of tau, and suggest that therapeutic strategies aimed at inhibiting this protease-dependent cleavage of Akt may prove beneficial in preventing tau hyperphosphorylation and subsequent neuropathology in AD and related tauopathies.
引用
收藏
页码:1002 / 1008
页数:7
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