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

Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermueller, Ulrike, Bansal, Vikas
et al (show 19 more authors) (2022) Medin co-aggregates with vascular amyloid-β in Alzheimer's disease. NATURE, 612 (7938). 123-+.

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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 age<sup>1,2</sup>, 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 dysfunction<sup>3</sup>. 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.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Transgenic, Humans, Mice, Alzheimer Disease, Amyloid beta-Protein Precursor, tau Proteins, Middle Aged, Amyloid beta-Peptides, Plaque, Amyloid, Cognitive Dysfunction
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 01 Dec 2022 10:36
Last Modified: 17 Oct 2023 17:12
DOI: 10.1038/s41586-022-05440-3
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