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@ARTICLE{Donner:821062,
      author       = {Donner, L. and Falker, K. and Gremer, L. and Klinker, S.
                      and Pagani, G. and Ljungberg, L. U. and Lothmann, K. and
                      Rizzi, F. and Schaller, M. and Gohlke, H. and Willbold, D.
                      and Grenegard, M. and Elvers, M.},
      title        = {{P}latelets contribute to amyloid-  aggregation in
                      cerebral vessels through integrin  {II}b 3-induced
                      outside-in signaling and clusterin release},
      journal      = {Science signaling},
      volume       = {9},
      number       = {429},
      issn         = {1937-9145},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {FZJ-2016-06306},
      pages        = {ra52 - ra52},
      year         = {2016},
      abstract     = {Cerebral amyloid angiopathy (CAA) is a vascular dysfunction
                      disorder characterized by deposits of amyloid-β (Aβ) in
                      the walls of cerebral vessels. CAA and Aβ deposition in the
                      brain parenchyma contribute to dementia and Alzheimer's
                      disease (AD). We investigated the contribution of platelets,
                      which accumulate at vascular Aβ deposits, to CAA. We found
                      that synthetic monomeric Aβ40 bound through its RHDS
                      (Arg-His-Asp-Ser) sequence to integrin αIIbβ3, which is
                      the receptor for the extracellular matrix protein
                      fibrinogen, and stimulated the secretion of adenosine
                      diphosphate (ADP) and the chaperone protein clusterin from
                      platelets. Clusterin promoted the formation of fibrillar Aβ
                      aggregates, and ADP acted through its receptors P2Y1 and
                      P2Y12 on platelets to enhance integrin αIIbβ3 activation,
                      further increasing the secretion of clusterin and Aβ40
                      binding to platelets. Platelets from patients with
                      Glanzmann's thrombasthenia, a bleeding disorder in which
                      platelets have little or dysfunctional αIIbβ3, indicated
                      that the abundance of this integrin dictated Aβ-induced
                      clusterin release and platelet-induced Aβ aggregation. The
                      antiplatelet agent clopidogrel, which irreversibly inhibits
                      P2Y12, inhibited Aβ aggregation in platelet cultures; in
                      transgenic AD model mice, this drug reduced the amount of
                      clusterin in the circulation and the incidence of CAA. Our
                      findings indicate that activated platelets directly
                      contribute to CAA by promoting the formation of Aβ
                      aggregates and that Aβ, in turn, activates platelets,
                      creating a feed-forward loop. Thus, antiplatelet therapy may
                      alleviate fibril formation in cerebral vessels of AD
                      patients.},
      cin          = {ICS-6},
      ddc          = {500},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000376467800003},
      pubmed       = {pmid:27221710},
      doi          = {10.1126/scisignal.aaf6240},
      url          = {https://juser.fz-juelich.de/record/821062},
}