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bioRxiv · 10.1101/2025.02.05.635937

Vascular amyloidβ load in the meningeal arterial network correlates with loss of cerebral blood flow and pial collateral vessel enlargement in the J20 murine model of Alzheimer's disease

Kaloss, A. M.·Browning, J. L.·Li, J.·Pan, Y.·Watsen, S.·Sontheimer, H.·Theus, M. H.·Olsen, M. L.
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Abstract

BackgroundGlobal reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimers disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network--a critical supplier of intracortical perfusion--has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD. MethodsUsing premortem delivery of Methoxy-XO4 to label A{beta}, and arterial vascular labeling, we assessed A{beta} burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice. ResultsWe show that 12-month-old J20 mice exhibit significant A{beta} deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with [~]40% vessel coverage in males and [~]20% in females--substantially exceeding A{beta} levels in cortical or hippocampal vessels. This vascular A{beta} burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by [~]15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden. ConclusionsThis is the first study to comprehensively characterize meningeal arterial A{beta} accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal A{beta} pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.

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Kaloss, A. M., Browning, J. L., Li, J., Pan, Y., Watsen, S., Sontheimer, H., Theus, M. H., Olsen, M. L.. 2025-02-06. Vascular amyloidβ load in the meningeal arterial network correlates with loss of cerebral blood flow and pial collateral vessel enlargement in the J20 murine model of Alzheimer's disease. https://doi.org/10.1101/2025.02.05.635937

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