%0 Journal Article
%T Cofilin promotes tau pathology in Alzheimer's disease.
%A Yan M
%A Tang L
%A Dai L
%A Lei C
%A Xiong M
%A Zhang X
%A He M
%A Tian Y
%A Xiong J
%A Ke W
%A Zhang Z
%A Zhang C
%A Deng X
%A Zhang Z
%J Cell Rep
%V 42
%N 2
%D 02 2023 28
%M 36807141
暂无%R 10.1016/j.celrep.2023.112138
%X 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.