Meningeal vascular Aβ deposition associates with cerebral hypoperfusion and compensatory collateral remodeling

TL;DR

This study shows that amyloid-beta builds up in brain blood vessels in a mouse model of Alzheimer's, leading to reduced blood flow and compensatory vessel changes.

Contribution

First comprehensive characterization of meningeal arterial Aβ accumulation in a preclinical model of vascular AD.

Findings

J20 mice show significant Aβ deposition in leptomeningeal arteries and pial collaterals, with sex differences in burden.

Vascular Aβ was linked to reduced cerebral blood flow and compensatory collateral vessel remodeling.

Findings mirror early-stage human AD and highlight the meningeal vasculature as a novel therapeutic target.

Abstract

Global reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimer’s 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.

Using premortem delivery of Methoxy-XO4 to label Aβ, and arterial vascular labeling, we assessed Aβ burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice.

We show that 12-month-old J20 mice exhibit significant Aβ deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with ~ 40% vessel coverage in males and ~ 20% in females—substantially exceeding Aβ levels in cortical or hippocampal vessels. This vascular Aβ 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.

This is the first study to comprehensively characterize meningeal arterial Aβ 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 Aβ 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.

The online version contains supplementary material available at 10.1186/s13195-025-01876-7.

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