Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease.
Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease.
复制标题
天冬酰胺内肽酶切割 tau 介导阿尔茨海默氏病的神经原纤维病理
作者：
神经原纤维缠结 (NFT) 由截短和过度磷酸化的 tau 蛋白组成，是包括阿尔茨海默病 (AD) 在内的许多与衰老相关的神经退行性疾病的共同特征。然而，衰老过程中介导 tau 截断和聚集的分子机制仍然难以捉摸。在这里，我们发现天冬酰胺内肽酶（AEP）是一种溶酶体半胱氨酸蛋白酶，在衰老过程中被激活，并通过蛋白水解降解 tau，消除其微管组装功能，诱导 tau 聚集，并引发神经退行性变。 AEP 在衰老过程中上调并活跃，并在 tau P301S 转基因小鼠和人类 AD 大脑中被激活，导致 NFT 中 tau 截短。删除 tau P301S 转基因小鼠的 AEP 可显着减少 tau 过度磷酸化，减轻突触损失并挽救受损的海马突触功能和认知缺陷。不可切割的 tau N255AN368A 突变体的感染可挽救 tau P301S 诱导的病理和行为缺陷。总之，这些观察结果表明，AEP 是神经退行性疾病中 tau 相关临床和神经病理学变化的关键介质。 AEP 的抑制可能对治疗 tau 介导的神经退行性疾病有治疗作用。
Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. AEP is upregulated and active during aging, and is activated in tau P301S transgenic mice and human AD brain, leading to tau truncation in NFTs. Deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates the synapse loss and rescues impaired hippocampal synaptic function and the cognitive deficits. Infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes in neurodegenerative diseases. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.
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DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
64.8
作者：
CACERES, A;KOSIK, KS
通讯作者：
KOSIK, KS
影响因子：
16
作者：
Liu, Zhixue;Jang, Sung-Wuk;Ye, Keqiang
通讯作者：
Ye, Keqiang