Student Theses and Dissertations
Cerebral Amyloid Angiopathy-Causing Beta-Amyloid Variants Have Altered Effects on the Clotting System
Date of Award
Doctor of Philosophy (PhD)
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 pathologies, including intracerebral hemorrhage (ICH) 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 normal wild-type (WT) Aβ and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, I investigated the role of the Aβ-fibrinogen interaction in HCAA pathology. My work revealed the most common forms of HCAA-linked mutations resulted in up to a 50-fold stronger binding affinity of Aβ for fibrinogen, increased perturbation of clot structure and fibrinolysis, and increased cortical fibrin(ogen)/Aβ co-deposition. Consistent with these in vitro results, HCAA patients have increased fibrin deposits compared to early-onset AD patients and non-demented individuals. In addition, because of the known WT Aβ enhancements to proteolytic/fibrinolytic system activation, I examined the effects of HCAA Aβ on the fibrinolytic system. I found that the majority of HCAA Aβ variants led to increased tPA-mediated plasminogen activation. The HCAA Arctic variant (E22G) did not, which may partially explain the unique clinical features of this mutation. To expand our understanding of the continuum of Aβs that can interact with fibrin(ogen) and the fibrinolytic system, I also explore the possible role of longer length Aβs in facets of AD-related vascular pathologies. My results suggest the HCAA-type mutations, with special emphasis on the Dutch and Iowa mutations, increase the interaction between Aβ, fibrinogen, and the fibrinolytic enzyme system. These findings provide a novel molecular mechanism for how CAA-linked mutations may lead to severe cerebrovascular pathology in HCAA patients by enhancing the Aβ-fibrin interaction and fibrinolytic activity.
Cajamarca, Steven, "Cerebral Amyloid Angiopathy-Causing Beta-Amyloid Variants Have Altered Effects on the Clotting System" (2021). Student Theses and Dissertations. 680.
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy