Plasma membrane repair defect in Alzheimer's disease neurons is driven by the reduced dysferlin expression.

Autor: Bulgart HR; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Lopez Perez MA; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Tucker A; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Giarrano GN; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Banford K; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Miller O; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Bonser SWG; Department of Applied Statistics and Research Methods, University of Northern Colorado, Greeley, Colorado, USA., Wold LE; Division of Cardiac Surgery, Department of Surgery, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Scharre D; Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Weisleder N; Department of Physiology & Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.; Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Oct 31; Vol. 38 (20), pp. e70099.
DOI: 10.1096/fj.202401731RR
Abstrakt: Alzheimer's disease (AD) is the most common neurodegenerative disease, and a defect in neuronal plasma membrane repair could exacerbate neurotoxicity, neuronal death, and disease progression. In this study, application of AD patient cerebrospinal fluid (CSF) and recombinant human Aβ to otherwise healthy neurons induces defective neuronal plasma membrane repair in vitro and ex vivo. We identified Aβ as the biochemical component in patient CSF leading to compromised repair capacity and depleting Aβ rescued repair capacity. These elevated Aβ levels reduced expression of dysferlin, a protein that facilitates membrane repair, by altering autophagy and reducing dysferlin trafficking to sites of membrane injury. Overexpression of dysferlin and autophagy inhibition rescued membrane repair. Overall, these findings indicate an AD pathogenic mechanism where Aβ impairs neuronal membrane repair capacity and increases susceptibility to cell death. This suggests that membrane repair could be therapeutically targeted in AD to restore membrane integrity and reduce neurotoxicity and neuronal death.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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