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

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. © 2022. The Author(s).

Citation

Jessica Wagner, Karoline Degenhardt, Marleen Veit, Nikolaos Louros, Katerina Konstantoulea, Angelos Skodras, Katleen Wild, Ping Liu, Ulrike Obermüller, Vikas Bansal, Anupriya Dalmia, Lisa M Häsler, Marius Lambert, Matthias De Vleeschouwer, Hannah A Davies, Jillian Madine, Deborah Kronenberg-Versteeg, Regina Feederle, Domenico Del Turco, K Peter R Nilsson, Tammaryn Lashley, Thomas Deller, Marla Gearing, Lary C Walker, Peter Heutink, Frederic Rousseau, Joost Schymkowitz, Mathias Jucker, Jonas J Neher. Medin co-aggregates with vascular amyloid-β in Alzheimer's disease. Nature. 2022 Dec;612(7938):123-131

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PMID: 36385530

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