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000165578 0247_ $$2doi$$a10.1038/s41586-022-05440-3
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000165578 1001_ $$0P:(DE-2719)2812193$$aWagner, Jessica$$b0$$eFirst author
000165578 245__ $$aMedin co-aggregates with vascular amyloid-β in Alzheimer's disease.
000165578 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2022
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000165578 520__ $$aAggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer's disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer's disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.
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000165578 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000165578 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000165578 650_7 $$2NLM Chemicals$$aSerum Amyloid A Protein
000165578 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000165578 650_2 $$2MeSH$$aHumans
000165578 650_2 $$2MeSH$$aAnimals
000165578 650_2 $$2MeSH$$aMice
000165578 650_2 $$2MeSH$$aMiddle Aged
000165578 650_2 $$2MeSH$$aAlzheimer Disease
000165578 650_2 $$2MeSH$$aAmyloid beta-Peptides
000165578 650_2 $$2MeSH$$aCognitive Dysfunction
000165578 650_2 $$2MeSH$$aPlaque, Amyloid
000165578 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor
000165578 650_2 $$2MeSH$$aMice, Transgenic
000165578 650_2 $$2MeSH$$aSerum Amyloid A Protein
000165578 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000165578 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000165578 650_2 $$2MeSH$$aPlaque, Amyloid: metabolism
000165578 650_2 $$2MeSH$$atau Proteins: metabolism
000165578 7001_ $$0P:(DE-2719)2810939$$aDegenhardt, Karoline$$b1$$eFirst author
000165578 7001_ $$0P:(DE-2719)9001638$$aVeit, Marleen$$b2
000165578 7001_ $$00000-0002-4030-1022$$aLouros, Nikolaos$$b3
000165578 7001_ $$00000-0002-0960-6274$$aKonstantoulea, Katerina$$b4
000165578 7001_ $$0P:(DE-2719)2810430$$aSkodras, Angelos$$b5
000165578 7001_ $$0P:(DE-2719)2811762$$aWild, Katleen$$b6
000165578 7001_ $$0P:(DE-2719)9002490$$aLiu, Ping$$b7$$udzne
000165578 7001_ $$0P:(DE-2719)2814201$$aObermüller, Ulrike$$b8
000165578 7001_ $$0P:(DE-2719)2812055$$aBansal, Vikas$$b9
000165578 7001_ $$0P:(DE-2719)2812478$$aDalmia, Anupriya$$b10
000165578 7001_ $$0P:(DE-2719)2811581$$aHäsler, Lisa M$$b11
000165578 7001_ $$0P:(DE-2719)2810762$$aLambert, Marius$$b12
000165578 7001_ $$aDe Vleeschouwer, Matthias$$b13
000165578 7001_ $$aDavies, Hannah A$$b14
000165578 7001_ $$00000-0001-9963-5871$$aMadine, Jillian$$b15
000165578 7001_ $$0P:(DE-2719)9001451$$aKronenberg-Versteeg, Deborah$$b16
000165578 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b17
000165578 7001_ $$aDel Turco, Domenico$$b18
000165578 7001_ $$aNilsson, K Peter R$$b19
000165578 7001_ $$aLashley, Tammaryn$$b20
000165578 7001_ $$aDeller, Thomas$$b21
000165578 7001_ $$aGearing, Marla$$b22
000165578 7001_ $$0P:(DE-2719)9000947$$aWalker, Lary C.$$b23
000165578 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b24
000165578 7001_ $$00000-0002-9189-7399$$aRousseau, Frederic$$b25
000165578 7001_ $$aSchymkowitz, Joost$$b26
000165578 7001_ $$0P:(DE-2719)2000010$$aJucker, Mathias$$b27
000165578 7001_ $$0P:(DE-2719)2811021$$aNeher, Jonas$$b28$$eLast author
000165578 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/s41586-022-05440-3$$gVol. 612, no. 7938, p. 123 - 131$$n7938$$p123 - 131$$tNature <London>$$v612$$x0028-0836$$y2022
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