Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Aging Cell. 2022 May;21(5):e13619. doi: 10.1111/acel.13619. Epub 2022 Apr 20.
Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C-terminal synapsin Ⅰ (83-705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild-type mice results in the production of the synapsin Ⅰ (83-705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP-generated synapsin Ⅰ (83-705) fragment in the hippocampus of tau P301S transgenic mice and wild-type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD.
突触功能障碍是阿尔茨海默病（AD）的一个关键特征。然而，突触功能障碍的分子机制仍不清楚。在这里，我们表明，突触蛋白Ⅰ是最重要的突触蛋白之一，被半胱氨酸蛋白酶天冬酰胺内肽酶（AEP）切割。AEP 在 AD 患者的大脑中在 N82 处切割突触蛋白Ⅰ，产生 C 端突触蛋白Ⅰ（83-705）片段。该片段在神经元中异常分布并诱导突触功能障碍。在野生型小鼠的海马体中过表达 AEP 会产生突触蛋白Ⅰ（83-705）片段，并诱导突触功能障碍和认知缺陷。此外，在 tau P301S 转基因小鼠和野生型小鼠的海马体中过表达 AEP 产生的突触蛋白Ⅰ（83-705）片段会促进突触功能障碍和认知缺陷。这些发现为 AD 中的突触功能障碍提供了一种新的机制。
