Medin co-aggregates with vascular amyloid-beta in Alzheimer's disease

• Type of Material: Article
• Authors: Jessica Wagner, German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE); Karoline Degenhardt, German Center for Neurodegenerative Diseases (DZNE); Marleen Veit, German Center for Neurodegenerative Diseases (DZNE); Nikolaos Louros, VIB-KU Leuven Center for Brain and Disease Research; Katerina Konstantoulea, VIB-KU Leuven Center for Brain and Disease Research; Angelos Skodras, German Center for Neurodegenerative Diseases (DZNE); Katleen Wild, German Center for Neurodegenerative Diseases (DZNE); Ping Liu, German Center for Neurodegenerative Diseases (DZNE); Ulrike Obermueller, University of Tübingen; Vikas Bansal, German Center for Neurodegenerative Diseases (DZNE); Anupriya Dalmia, German Center for Neurodegenerative Diseases (DZNE); Lisa M Häsler, German Center for Neurodegenerative Diseases (DZNE); Marius Lambert, German Center for Neurodegenerative Diseases (DZNE); Matthias De Vleeschouwer, VIB-KU Leuven Center for Brain and Disease Research; Hannah A Davies, University of Liverpool; Jillian Madine, University of Liverpool; Deborah Kronenberg-Versteeg, German Center for Neurodegenerative Diseases (DZNE); Regina Feederle, Helmholtz Zentrum Munchen; Domenico Del Turco, Goethe University; Peter KR Nilsson, Linkoping University; Tammaryn Lashley, University College London; Thomas Deller, Goethe University; Marla Gearing, Emory University; Lary Walker, Emory University; Peter Heutink, German Ctr Neurodegenerat Dis DZNE; Frederic Rousseau, VIB-KU Leuven Center for Brain and Disease Research; Joost Schymkowitz, VIB-KU Leuven Center for Brain and Disease Research; Mathias Jucker, German Center for Neurodegenerative Diseases (DZNE); Jonas J Neher, German Center for Neurodegenerative Diseases (DZNE)
• Language: English
• Date: 2022-11-16
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05440-3
• Title of Journal or Parent Work: NATURE
• Volume: 612
• Issue: 7938
• Start Page: 123
• End Page: +
• Grant/Funding Information: Open access funding provided by Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE) in der Helmholtz-Gemeinschaft.
• Keywords: NETWORK; ANGIOPATHY; A-BETA; PEPTIDE; BRAIN; Multidisciplinary Sciences; PATHOLOGY; MOUSE MODELS; MICE; Science & Technology - Other Topics; DEPOSITION; PROVIDES; Science & Technology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.