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

Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14482-14492. doi: 10.1073/pnas.1921327117. Epub 2020 Jun 9.


Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aβ) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (Aβ) peptide cause an increase in vascular deposits. Since the interaction between Aβ and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aβ-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aβ for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aβs led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/Aβ codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aβ, which might be central to cerebrovascular pathologies observed in HCAA.

Keywords: fibrinogen; fibrinolysis; hereditary cerebral amyloid angiopathy; β-amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Brain / pathology*
  • Cerebral Amyloid Angiopathy, Familial / genetics
  • Cerebral Amyloid Angiopathy, Familial / pathology*
  • Female
  • Fibrin / metabolism*
  • Fibrinogen / isolation & purification
  • Fibrinogen / metabolism*
  • Fibrinolysis / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Protein Binding / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism


  • Amyloid beta-Peptides
  • Peptide Fragments
  • Recombinant Proteins
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Fibrin
  • Fibrinogen