Viral-Induced Amyloidogenic Potentiation: Investigating SARS-CoV-2 Spike Protein as a Driver of CAA Pathology in rTg-D Rats

Document Type

Poster

Date of Original Version

3-27-2026

Abstract

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease characterized by the deposition of β-amyloid (Aβ) primarily in the walls of small and medium sized cerebral aterioles, arising from cleavage of amyloid precursor protein (APP). CAA is a significant comorbidity of Alzheimer's disease (AD), and is independently associated with microbleeds, lobar intracerebral hemorrhage, stroke, and cognitive decline — particularly in elderly populations. Despite its prevalence, CAA remains underdiagnosed: neuropathological assessment identifies CAA in 48% of AD patients and 23% of the general population, compared to only 22% and 7%, respectively, by MRI-based detection, suggesting the true burden of disease is substantially greater than current clinical estimates reflect. Emerging evidence implicates SARS-CoV-2 infection as a potential contributor to amyloid pathology and cerebrovascular injury. COVID-19 patients exhibit cerebral petechial hemorrhages and microthrombi at autopsy, consistent with SARS-CoV-2-induced endothelitis and broader vasculopathic changes. Separately, patients with COVID-19-associated neurological syndromes demonstrate significantly reduced CSF levels of soluble APP (sAPPα, sAPPβ), Aβ40, and Aβ42 (indicative of disrupted amyloid processing) alongside elevated neuroinflammatory markers. Furthermore, a fragment of the SARS-CoV-2 spike protein has been shown to promote Aβ aggregation and toxicity in vitro, raising the possibility that viral infection directly accelerates amyloidogenic pathogenesis. Together, these findings support a mechanistic hypothesis in which SARS-CoV-2 infection, through neuroinflammation, vascular injury, and altered APP processing, may potentiate CAA onset or progression. To investigate this relationship, we utilize the rTg-D transgenic rat model, developed at the University of Rhode Island, which expresses the human familial Dutch E22Q mutant Aβ and develops progressive arteriolar CAA type-2. Critically, rTg-D rats reliably develop cerebral microhemorrhagic vasculopathies alongside small vessel occlusions and calcifications that are consistently localized to the thalamic region — a pattern that mirrors pathological features observed in human Dutch-type CAA. This regional reproducibility and the model's reflection of human vascular disease states make it uniquely suited to detect and characterize changes in CAA pathology progression following SARS-CoV-2 exposure. Following SARS-CoV-2 spike protein administration in rTg-D rats at 4 M of age we plan to conduct quantitative immunohistochemical analysis of cerebral vascular Aβ and associated vasculopathies.

This document is currently not available here.

Share

COinS