Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen

Since the interaction between Aβ and fibrinogen increases Cerebral amyloid angiopathy and plays an important role in cerebrovascular damage in Alzheimer’s disease, we investigated the role of the Aβ–fibrinogen interaction in Hereditary cerebral amyloid angiopathy pathology

Steven A. Cajamarca; Erin H. Norris; Louise van der Weerd; Sidney Strickland; Hyung Jin Ahn


Scholarcy highlights

  • Cerebral amyloid angiopathy, where beta-amyloid deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer’s disease patients
  • While CAA is mostly observed in the sporadic form of AD patients in late adulthood, rare familial forms occur in midadulthood and lead to more severe cerebrovascular disease, including severe strokes, early onset dementia, and death
  • Most AD-linked amyloid precursor protein mutations elevate total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to hereditary cerebral amyloid angiopathy cause a dramatic increase in vascular deposits of Aβ
  • We report high levels of mutant Aβ-fibrin(ogen) codeposition in Hereditary cerebral amyloid angiopathy-Dutch and -Iowa patient postmortem occipital brain tissue, especially at cerebral blood vessel sites with a high burden of CAA pathology, which may be explained by stronger interaction between HCAA Aβ and fibrinogen
  • Our in vitro findings show that the presence of Dutch- and Iowa-mutant Aβs leads to the formation of fibrin clots that are more structurally altered and more resistant to plasmin-mediated fibrinolysis compared to WT Aβ-induced clots
  • The increased binding affinity between HCAA Aβs and fibrinogen could be explained by the increased aggregation propensity featured by the mutant Aβs and/or the HCAA-linked amino acid substitutions
  • NAB61 was able to detect parenchymal plaques in Hereditary cerebral amyloid angiopathy-Dutch and early-onset AD brains, its specificity in detecting vascular Aβ oligomers, including in larger and smaller vessels, highlighted the role cerebrovascular mutant Aβ oligomers have in their interaction and codeposition with fibrin(ogen) along cerebral vessel of various sizes

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