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@ARTICLE{Wagner:165578,
      author       = {Wagner, Jessica and Degenhardt, Karoline and Veit, Marleen
                      and Louros, Nikolaos and Konstantoulea, Katerina and
                      Skodras, Angelos and Wild, Katleen and Liu, Ping and
                      Obermüller, Ulrike and Bansal, Vikas and Dalmia, Anupriya
                      and Häsler, Lisa M and Lambert, Marius and De Vleeschouwer,
                      Matthias and Davies, Hannah A and Madine, Jillian and
                      Kronenberg-Versteeg, Deborah and Feederle, Regina and Del
                      Turco, Domenico and Nilsson, K Peter R and Lashley, Tammaryn
                      and Deller, Thomas and Gearing, Marla and Walker, Lary C.
                      and Heutink, Peter and Rousseau, Frederic and Schymkowitz,
                      Joost and Jucker, Mathias and Neher, Jonas},
      title        = {{M}edin co-aggregates with vascular amyloid-β in
                      {A}lzheimer's disease.},
      journal      = {Nature},
      volume       = {612},
      number       = {7938},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DZNE-2022-01718},
      pages        = {123 - 131},
      year         = {2022},
      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.},
      keywords     = {Alzheimer Disease: metabolism / Humans / Animals / Mice /
                      Middle Aged / Alzheimer Disease / Amyloid beta-Peptides /
                      Cognitive Dysfunction / Plaque, Amyloid / Amyloid
                      beta-Protein Precursor / Mice, Transgenic / Serum Amyloid A
                      Protein / Amyloid beta-Peptides: metabolism / Amyloid
                      beta-Protein Precursor: metabolism / Plaque, Amyloid:
                      metabolism / tau Proteins: metabolism / Amyloid
                      beta-Peptides (NLM Chemicals) / Amyloid beta-Protein
                      Precursor (NLM Chemicals) / Serum Amyloid A Protein (NLM
                      Chemicals)},
      cin          = {AG Neher / AG Jucker / AG Heutink / AG Feederle},
      ddc          = {500},
      cid          = {I:(DE-2719)1210012 / I:(DE-2719)1210001 /
                      I:(DE-2719)1210002 / I:(DE-2719)1140004},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 354 - Disease
                      Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36385530},
      pmc          = {pmc:PMC9712113},
      doi          = {10.1038/s41586-022-05440-3},
      url          = {https://pub.dzne.de/record/165578},
}