# Induction of Neutrophil Extracellular Traps by Beta-Amyloid Deposits in Cerebral Amyloid Angiopathy

> **NIH NIH R03** · UNIVERSITY OF RHODE ISLAND · 2024 · $157,500

## Abstract

Cerebral amyloid angiopathy (CAA), a disease with no available treatments, is a prevalent Alzheimer’s
disease related disorder (ADRD), occurring as a comorbidity in > 80% of Alzheimer’s disease (AD)
cases, but also sporadically in > 50% of people over the age of 80 years. Arising from fibrillar amyloid
β (Aβ) deposition in cortical arteries and arterioles and brain capillaries, CAA is marked clinically by
cerebral infarction, microbleeds and intracerebral hemorrhages (ICH), pronounced perivascular
neuroinflammation, and is a prominent contributor to vascular cognitive impairment and dementia. CAA
severity strongly correlates with cognitive decline in sporadic CAA and AD. Despite the severe clinical
burden, mechanisms linking vascular Aβ deposition to microthrombus, vascular damage, and
inflammation are poorly understood, and there are no available treatments for CAA. Investigation
of these mechanisms in reliable animal models is critical, and the rTg-DI rat, that faithfully recapitulates
human CAA pathologies, including progressive vascular Aβ deposition, pronounced perivascular
neuroinflammation, and thrombotic events/microbleeds, is such a model. Neutrophil mediated
inflammatory mechanisms, such as neutrophil extracellular traps (NETs) have been reported in
cardiovascular disease, and various chronic inflammatory disorders, including AD patient brains. NET
formation often leads to thrombin generation, thrombotic events, and vascular damage like that seen
in CAA and may be an important component of Aβ related vascular damage and neuroinflammation.
Recently we demonstrated the presence of NET markers in brain regions containing microhemorrhages
and thrombotic events in the rTg-DI rat model of CAA and defined a proteomic signature of NET
formation in early and late disease stages. Based on this strong evidence, our central hypothesis is
that NETs are directly induced by vascular Aβ fibril deposits and NETs forming either
luminally or abluminally may contribute to vascular degeneration prior to microbleed
occurrence in CAA. Here we will investigate CAA-specific fibrillar Aβ’s ability to induce NET formation
in-vitro, including NET visualization, quantitation, and molecular characterization by proteomic and
transcriptomic analysis. We will also chronologize neutrophil and NET involvement in CAA progression
by investigation of neutrophil and NET presence in cerebral blood vessels and surrounding tissue, in
early and late disease stages, using cerebral vessel and brain regional isolation, proteomics and
targeted transcriptomics, and immunohistological approaches. This study will provide important insight
to currently unknown mechanisms of CAA progression and investigate the potential of finding targets
within the NET pathway for therapeutic intervention in CAA.

## Key facts

- **NIH application ID:** 10789290
- **Project number:** 1R03AG085082-01
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Joseph M Schrader
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $157,500
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789290

## Citation

> US National Institutes of Health, RePORTER application 10789290, Induction of Neutrophil Extracellular Traps by Beta-Amyloid Deposits in Cerebral Amyloid Angiopathy (1R03AG085082-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10789290. Licensed CC0.

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