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RNA sequencing data reveal elevated expression of Vim in AD brains, with its aggregation frequently observed around amyloid-\u03b2 (A\u03b2) plaques. However, the precise mechanisms by which Vim influences the aggregation or propagation of A\u03b2 plaques remain unclear. In this study, we detected the upregulation of astrocytic Vim in AD brain tissue, with its co-localization around A\u03b2 plaques. Asparagine endopeptidase (AEP), another molecule implicated in AD, was found to cleave Vim both in vitro and in vivo, including within human brain tissue. Mass spectrometry analysis confirmed that the AEP cleavage site on Vim is located at N283. We further investigated the in vivo cellular localization of Vim and observed that fragmented Vim, particularly the C-terminal fragment Vim 284\u2013466, promotes apoptosis and disrupts the network structure that is essential for interaction with glial fibrillary acidic protein (GFAP). This disruption impairs astrocytic phagocytosis of exogenous A\u03b2, which is attributed to the reduced release of apolipoprotein E (ApoE) by astrocytes. The decrease in ApoE levels, in turn, diminishes the transport and clearance of A\u03b2. Conversely, mutation of the Vim N283 site (N283A) prevents AEP-mediated cleavage of Vim, preserves the GFAP network structure, restores ApoE levels, and reverses the effects on A\u03b2 aggregation. Collectively, our findings elucidate the role of Vim fragmentation in A\u03b2 plaque deposition and propose a potentially novel therapeutic strategy for Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ijms26072857","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T10:10:08Z","timestamp":1742551808000},"page":"2857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Vimentin Fragmentation and Its Role in Amyloid-Beta Plaque Deposition in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Lan","family":"Zhang","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3780-2694","authenticated-orcid":false,"given":"Ji","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalong","family":"Yan","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Xiang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective 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China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuran","family":"Gui","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan 430056, China"},{"name":"Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, 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