Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease
Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease
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DOI：
10.1073/pnas.1630428100
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发表时间：
2003-08-19
影响因子：
11.1
通讯作者：
Cryns, VL
中科院分区：
文献类型：
--
作者：
Gamblin, TC;Chen, F;Cryns, VL
阿尔茨海默病 (AD) 的主要病理特征是细胞外淀粉样斑块和细胞内神经原纤维缠结，后者由微管结合蛋白 tau 组装成配对的螺旋和直丝组成。最近的研究表明，这些病理实体可能在功能上相关，尽管淀粉样蛋白沉积促进病理性 tau 丝组装的机制尚不清楚。在此，我们报告在体外和用淀粉样蛋白-β (Abeta) (1-42) 肽处理的神经元中，tau 在其 C 末端高度保守的天冬氨酸残基 (Asp(421)) 处被多个半胱天冬酶蛋白水解。在 Abeta 处理的神经元中，Tau 在 Asp(421) 处快速裂解（2 小时内），并且其蛋白水解似乎先于细胞凋亡的核事件。我们还证明，半胱天冬酶切割 tau 会产生一种截短的蛋白质，该蛋白质缺乏 C 端 20 个氨基酸，并且在体外比野生型 tau 更快、更广泛地组装成 tau 丝。使用特异性识别 Asp421 处截短的 tau 蛋白的单克隆抗体，我们发现在 AD 脑纤维状病变中，tau 蛋白在该位点被蛋白水解切割。总而言之，我们的结果表明了一种将 AD 中淀粉样蛋白沉积和神经原纤维缠结联系起来的新机制：Abeta 肽通过触发 tau 的半胱天冬酶裂解并产生具有增强聚合动力学的蛋白水解产物，促进神经元中病理性 tau 丝组装。
The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp(421)) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp(421) in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.