Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction

• Type of Material: Article
• Authors: Xingyu Zhang, Renmin Hospital of Wuhan University; Li Zou, Renmin Hospital of Wuhan University; Lanxia Meng, Renmin Hospital of Wuhan University; Min Xiong, Renmin Hospital of Wuhan University; Lina Pan, Renmin Hospital of Wuhan University; Guiqin Chen, Emory University; Yonga Zheng, Renmin Hospital of Wuhan University; Jing Xiong, Renmin Hospital of Wuhan University; Zhihao Wang, Emory University; Duc M Duong, Emory University; Zhaohui Zhang, Renmin Hospital of Wuhan University; Xuebing Cao, Huazhong University of Science & Technology; Tao Wang, Huazhong University of Science & Technology; Li Tang, Wuhan University; Keqiang Ye, Emory University; Zhentao Zhang, Emory University
• Language: English
• Date: 2021-05-21
• Publisher: ELIFE SCIENCES PUBLICATIONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2021, Zhang et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.65301
• Title of Journal or Parent Work: ELIFE
• Volume: 10
• Grant/Funding Information: National Natural Science Foundation of China 81822016 to Zhentao Zhang.; This paper was supported by the following grants:; National Natural Science Foundation of China 81771382 to Zhentao Zhang.
• Keywords: PHOSPHORYLATION; CLATHRIN; Biology; ALZHEIMERS-DISEASE; PROTEIN; Science & Technology; COGNITIVE DECLINE; Life Sciences & Biomedicine; P35; VESICLE ENDOCYTOSIS; Life Sciences & Biomedicine - Other Topics; DYNAMIN; CDK5; NEUROFIBRILLARY TANGLES
• Research Categories: Health Sciences, Pathology

Abstract

Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer’s disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.