Cofilin promotes tau pathology in Alzheimer’s disease
Mingmin Yan,
Li Tang,
Lijun Dai,
Chuntao Lei,
Min Xiong,
Xingyu Zhang,
Mingyang He,
Ye Tian,
Jing Xiong,
Wei Ke,
Zhaohui Zhang,
Chun Zhang,
Xiaorong Deng,
Zhentao Zhang
Affiliations
Mingmin Yan
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Neurology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430060, China
Li Tang
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Lijun Dai
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Chuntao Lei
Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430060, China
Min Xiong
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Xingyu Zhang
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Mingyang He
Hubei Provincial Institute for Food Supervision and Test, Wuhan 430060, China
Ye Tian
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Jing Xiong
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Wei Ke
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Zhaohui Zhang
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China
Chun Zhang
Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430060, China
Xiaorong Deng
Department of Neurology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430060, China
Zhentao Zhang
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Corresponding author
Summary: 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.
