Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermueller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Haesler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, Peter, Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, Neher, Jonas J., Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermueller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Haesler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, Peter, Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, and Neher, Jonas J.
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(1,)(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 dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta 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-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers 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-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta 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-beta deposition in the blood vessels of the brain., Funding Agencies|Deutsche Forschungsgemeinschaft (DFG) [NE 1951/2-1, NE 1951/2-2, JU655/4-1]; EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (IMPRiND grant) [116060]; Hans und Ilse Breuer-Stiftung; China Scholarship Council; FEBS short term travel fellowship; British Heart Foundation Intermediate Basic Science fellowship [FS/12/61/29877]; Swedish Research Council; Flanders Institute for Biotechnology (VIB) [C0401]; Fund for Scientific Research Flanders (FWO) [G0C3522N, 12P0919N, 12P0922N]; Stichting Alzheimer Onderzoek/Fondation Recherche Alzheimer [SAO-FRA 2020/0013]; Alzheimers Research UK senior fellowship; Alexander von Humboldt Foundation research fellowship; NIA [P30AG10161, R01AG15819, R01AG17917, U01AG46152, U01AG61356, P50AG025688]; Illinois Department of Public Health (ROSMAP); Translational Genomics Research Institute