Cofilin promotes tau pathology in Alzheimer’s disease
Mingmin Yan, Li Tang, Lijun Dai, Chun‐Tao Lei, Min Xiong, Xingyu Zhang, Mingyang He, Ye Tian, Jing Xiong, Wei Ke, Zhaohui Zhang, Zhaohui Zhang, Chun Zhang, Xiaorong Deng, Zhentao Zhang, Zhentao Zhang
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.