Saturday, September 7, 2024
9/7/2024
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.
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