Vicious circle of amyloid and leptomeningeal macrophages evokes vascular dysfunction in CAA

Abstract

The subarachnoid space contains leptomeningeal arteries and resident immune cells known as subarachnoid macrophages (SAMs). In Alzheimers disease (AD) and related cerebral amyloid angiopathy, amyloid-{beta} (A{beta}) frequently accumulates around the leptomeningeal arteries. Nevertheless, the local immune responses and their functional consequences remain poorly understood. Using longitudinal intravital imaging in a mouse model of AD, we tracked A{beta} deposition and identified a distinct SAM population that migrates to and phagocytoses these arterial A{beta} deposits. SAM recruitment correlated with vascular remodeling, including smooth muscle loss, aneurysm formation, and reduced cerebral perfusion. Transcriptomic profiling revealed a distinct SAM population in AD with upregulated CD39 expression. Pharmacological inhibition of CD39 attenuated arterial A{beta} deposition, identifying SAMs as a potential therapeutic target in AD.