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

• Published in: The FASEB journal Vol. 38; no. 20; pp. e70099 - n/a
• Main Authors: Bulgart, Hannah R., Lopez Perez, Miguel A., Tucker, Alexis, Giarrano, Gianni N., Banford, Kassidy, Miller, Olivia, Bonser, Sidney W. G., Wold, Loren E., Scharre, Douglas, Weisleder, Noah
• Format: Journal Article
• Language: English
• Published: United States 31.10.2024
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Autophagy; Cell Membrane - metabolism; dysferlin; Dysferlin - genetics; Dysferlin - metabolism; Female; Humans; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; membrane repair; neurodegeneration; Neurons - metabolism; neurodegeneration; autophagy; dysferlin; Alzheimer's disease; membrane repair
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202401731RR

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. Amyloid beta expression and treatment reduce dysferlin expression in Alzheimer's disease neurons. This reduction in dysferlin expression contributes to reduced membrane repair capacity. Dysferlin protein expression is reduced because of overactive autophagy that can be blocked with an autophagy inhibitor.