 Medin co-aggregates with vascular amyloid-β in Alzheimer’s diseaseJessica 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 Vleeschouwer,
Hannah A. Davies,
Jillian Madine,
Deborah Kronenberg-Versteeg,
Regina Feederle,
Domenico Turco,
K. Peter R. Nilsson,
Tammaryn Lashley,
Thomas Deller,
Marla Gearing,
Lary C. Walker,
Peter Heutink,
Frederic Rousseau,
Joost Schymkowitz,
Mathias Jucker and
Jonas J. Neher ()
Nature, 2022, vol. 612, issue 7938, 123-131 Abstract: 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. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:612:y:2022:i:7938:d:10.1038_s41586-022-05440-3 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-05440-3 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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