Document Type

Poster

Date of Original Version

3-27-2026

Abstract

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the progressive deposition of amyloid-β (Aβ) peptides within the walls of small to medium-sized cerebral blood vessels. As a prevalent comorbidity of Alzheimer's disease, CAA disproportionately affects the aging population, with an estimated 25% of individuals over 50 and approximately 50% of those over 80 exhibiting moderate to severe pathology. The condition is clinically significant due to its strong associations with microbleeds, intracranial hemorrhage, and cognitive decline. At the molecular level, Aβ accumulation arises from the irregular cleavage of amyloid precursor protein (APP), disrupting vascular integrity and triggering downstream pathological cascades. To elucidate the neuroimmune mechanisms underlying CAA progression, we employed the preclinical transgenic rTg-DI rat model, which recapitulates an age-dependent pattern of vascular Aβ deposition most prominently in the thalamus, with additional involvement of the hippocampus and cortex. This model hosts a double-mutation in humanized-APP, known as the Dutch and Iowa mutations respectfully, which lends itself to the formation of CAA-type 2. Using this model, we investigated the contribution of innate immune effectors, specifically neutrophils and neutrophil extracellular traps (NETs), to disease pathology. NETs, which function as molecular scaffolds for thrombus formation, are web-like structures that form the exocytosis of nucleic acids and proteolytic enzymes, used in innate immune defense. NETs are well-established mediators of platelet activation, coagulation, and sterile inflammation, positioning them as potentially important drivers of CAA-associated vascular and neuroinflammatory injury. Immunohistochemical analyses revealed the presence of established NET markers: citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE) within regions of active pathology. This study provides the first evidence of NET formation in the context of CAA, providing a key insight to CAA progression and pathology. Complementary microglial labeling further demonstrated robust recruitment and activation of resident brain macrophages in affected areas, highlighting a broader neuroinflammatory response to vascular Aβ deposition. Collectively, these findings implicate neutrophil-driven innate immune signaling as a novel and underexplored axis of CAA pathophysiology, with important implications for future therapeutic targeting. We hypothesize that structurally distinct Aβ fibril species differentially modulate neutrophil recruitment and the induction of NETosis, driving pathological outcomes with varying potencies. Furthermore, we propose that NETosis-derived molecular scaffolds actively contribute to the formation of thrombotic occlusions and the progressive deterioration of cerebral vascular integrity, establishing neutrophil-mediated innate immune activation as a central and mechanistically significant driver of CAA pathogenesis. Future directions for this project will focus on two complementary investigative strategies. First, we will establish an in vitro model of NETosis through the direct stimulation of neutrophils with structurally defined Aβ fibril species, enabling mechanistic dissection of the fibril-neutrophil interaction and quantitative comparison of NETosis induction across distinct Aβ conformations. Second, we will employ targeted pharmacological inhibition of NETosis, using established NET-blocking agents, to causally evaluate the contribution of NETs to CAA progression in the rTg-DI rat model. Together, these approaches will provide both mechanistic insight into how Aβ fibrils drive innate immune activation and therapeutic proof-of-concept for NETosis inhibition as a viable intervention strategy in CAA.

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