CEREBRAL VASCULAR AMYLOID SEEDS DRIVE AMYLOID SS-PROTEIN FIBRIL ASSEMBLY WITH A DISTINCT ANTI-PARALLEL STRUCTURE

Abstract

Cerebrovascular accumulation of the amyloid beta-protein (Abeta), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer’s disease. Additionally, familial forms of CAA, with specific Abeta mutations such as Dutch E22Q and Iowa D23N, cause severe cerebral vascular accumulation of amyloid that serves as a potent and early driver of vascular cognitive impairment and dementia (VCID). The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here we investigated how cerebral vascular fibrillar amyloid seeds influence the assembly, accumulation and structure of Abeta. A combination of biochemical and biophysical approaches were used to study amyloid fibril formation in vitro. Transgenic mice were then used in conjunction with quantitative pathological, biochemical and structural analyses to study how CAA mutant and wild-type Abeta interact in brain to drive vascular amyloid formation. In the in vitro that CAA mutant amyloid fibril seeds can adopt a parallel or anti-parallel configuration and that both can promote rapid fibril assembly of wild-type Abeta peptides that adopt corresponding fibrillar signatures. In the in vivo studies we first show that intrahippocampal administration of biotin-labeled wild-type Abeta peptides strongly accumulate on pre-existing cerebral microvascular amyloid deposits in Tg-SwDI mice, a model that preferentially develops early-onset CAA mutant microvascular amyloid. Subsequently, we crossed Tg-SwDI mice with Tg2576 mice, a model that produces high amounts of human wild-type Abeta in brain. The bigenic mice exhibited markedly elevated accumulation of microvascular fibrillar amyloid in brain compared to either single transgenic line that was largely composed of human wild-type Abeta. Further, isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Abeta into distinct anti-parallel amyloid fibrils. These findings indicate that cerebral vascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Abeta into a unique structure that likely contributes to its distinctive pathology.