Aβ peptide and fibrinogen weave a web of destruction in cerebral amyloid angiopathy

Abstract

Alzheimer’s disease (AD) is characterized by disruption of the normal brain architecture which is driven by the formation of two pathological structures, including senile plaques and neurofibrillary tangles. The amyloid-β (Aβ) peptide, derived from Aβ precursor protein (AβPP), is the major component of senile plaques in the brain and cerebrovasculature. Substantial evidence has demonstrated that the Aβ peptide is a major contributor to the neurodegenerative process, acting through local neurotoxic and inflammatory processes (1). Cerebral amyloid angiopathy (CAA) is a common pathological feature of AD and results from Aβ deposits in and around cerebral blood vessels that are believed to mediate disruption of the brain vasculature. Importantly, Aβ does not act alone, but rather it exerts pathophysiological effects by forming complexes with the blood-clotting protein fibrinogen (2). Although an association between Aβ and fibrinogen has been appreciated for over a decade, the molecular features of this interaction as well as the precise downstream consequences have been a significant knowledge gap. CAA is routinely observed in spontaneous AD that afflicts individuals late in adulthood. However, there are familial forms of CAA that are appreciated earlier in life and lead to exacerbated cerebrovascular disease. Indeed, a subset of inherited Aβ mutations specifically promote more pronounced vascular Aβ deposits, resulting in a condition termed hereditary cerebral amyloid angiopathy (HCAA). To better characterize molecular mechanisms mediating CAA, Cajamarca et al. (3) have analyzed Aβ deposition and the association with fibrinogen in the context of the most common forms of HCAA, including Aβ Dutch (E22Q) and Iowa (D23N). The hypothesis that Aβ and fibrinogen form a pathological nexus extends back to the first observations that fibrin(ogen) accumulates and colocalizes with Aβ plaques as observed in postmortem brain tissues of AD patients (2, 4). A direct functional contribution of fibrinogen to AD pathogenesis has been … [↵][1]1To whom correspondence may be addressed. Email: matthew_flick{at}med.unc.edu. [1]: #xref-corresp-1-1