Abstract：
The molecular mechanisms mediating the aggregation and transmission of tau in AD remain unclear. Here, we show that the actin-binding protein cofilin is cleaved by a cysteine protease asparagine endopeptidase (AEP) at N138 in the brains of patients with AD. The AEP-generated cofilin 1-138 fragment interacts with tau and promotes its aggregation. The mixed fibrils consisting of cofilin 1-138 and tau are more pathogenic to cells than pure tau fibrils. Furthermore, overexpression of cofilin 1-138 in the brain facilitates the propagation of pathological tau aggregates and promotes AD-like cognitive impairments in tau P301S mice. However, mice infected with adeno-associated viruses (AAVs) encoding an AEP-uncleavable cofilin mutant show attenuated tau pathology and cognitive impairments compared with mice injected with AAVs encoding wild-type cofilin. Together, these observations support the role of the cofilin 1-138 fragment in the aggregation and transmission of tau pathology during the onset and progression of AD.
摘要：
介导tau在AD中聚集和传播的分子机制尚不清楚。这里,我们显示，肌动蛋白结合蛋白cofilin被半胱氨酸蛋白酶天冬酰胺内肽酶（AEP）在AD患者的大脑中N138处裂解。AEP生成的cofilin1-138片段与tau相互作用并促进其聚集。由cofilin1-138和tau组成的混合原纤维比纯tau原纤维对细胞更具致病性。此外，脑中cofilin1-138的过表达促进病理性tau聚集体的繁殖，并促进tauP301S小鼠的AD样认知障碍。然而,与注射编码野生型cofilin的AAV的小鼠相比,用编码AEP-不可切割的cofilin突变体的腺相关病毒(AAV)感染的小鼠显示出减弱的tau病理学和认知障碍。一起,这些观察结果支持cofilin1-138片段在AD发作和进展期间tau病理的聚集和传播中的作用.
