TY  - JOUR
AU  - Wagner, Jessica
AU  - Degenhardt, Karoline
AU  - Veit, Marleen
AU  - Louros, Nikolaos
AU  - Konstantoulea, Katerina
AU  - Skodras, Angelos
AU  - Wild, Katleen
AU  - Liu, Ping
AU  - Obermüller, Ulrike
AU  - Bansal, Vikas
AU  - Dalmia, Anupriya
AU  - Häsler, Lisa M
AU  - Lambert, Marius
AU  - De Vleeschouwer, Matthias
AU  - Davies, Hannah A
AU  - Madine, Jillian
AU  - Kronenberg-Versteeg, Deborah
AU  - Feederle, Regina
AU  - Del Turco, Domenico
AU  - Nilsson, K Peter R
AU  - Lashley, Tammaryn
AU  - Deller, Thomas
AU  - Gearing, Marla
AU  - Walker, Lary C.
AU  - Heutink, Peter
AU  - Rousseau, Frederic
AU  - Schymkowitz, Joost
AU  - Jucker, Mathias
AU  - Neher, Jonas
TI  - Medin co-aggregates with vascular amyloid-β in Alzheimer's disease.
JO  - Nature 
VL  - 612
IS  - 7938
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DZNE-2022-01718
SP  - 123 - 131
PY  - 2022
AB  - 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.
KW  - Alzheimer Disease: metabolism
KW  - Humans
KW  - Animals
KW  - Mice
KW  - Middle Aged
KW  - Alzheimer Disease
KW  - Amyloid beta-Peptides
KW  - Cognitive Dysfunction
KW  - Plaque, Amyloid
KW  - Amyloid beta-Protein Precursor
KW  - Mice, Transgenic
KW  - Serum Amyloid A Protein
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Plaque, Amyloid: metabolism
KW  - tau Proteins: metabolism
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Serum Amyloid A Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36385530
C2  - pmc:PMC9712113
DO  - DOI:10.1038/s41586-022-05440-3
UR  - https://pub.dzne.de/record/165578
ER  -