Cerebral amyloid angiopathy (CAA), the deposition of -amyloid (A) peptides in leptomeningeal and cortical blood vessels, affects the majority of patients with Alzheimer's disease (AD). Evidence suggests that vascular amyloid deposits may result from impaired clearance of neuronal A along perivascular spaces. We investigated the role of perivascular macrophages in regulating CAA severity in the TgCRND8 mouse model of AD. Depletion of perivascular macrophages significantly increased the number of thioflavin S-positive cortical blood vessels. ELISA confirmed that this increase was underscored by elevations in total vascular A 42 levels. Conversely, stimulation of perivascular macrophage turnover reduced cerebral CAA load, an effect that was not mediated through clearance by microglia or astrocytes. These results highlight a function for the physiological role of perivascular macrophages in the regulation of CAA and suggest that selective targeting of perivascular macrophage activation might constitute a therapeutic strategy to clear vascular amyloid.A s many as 90% of all Alzheimer's disease (AD) cases present with cerebral amyloid angiopathy (CAA), the deposition of -amyloid (A) in cortical and leptomeningeal blood vessels (1). The vascular A deposits observed in AD have been shown in vitro to induce degeneration of human and murine cerebrovascular smooth muscle and endothelial cells and in vivo to inhibit angiogenesis, impair vascular tone, and decrease total cerebral blood flow (2, 3). Pathological examination of AD brains positive for CAA has revealed capillary fragmentation, thickening, and reduplication of vascular basement membranes and disruption of bloodbrain barrier (BBB) permeability (4). More recently it has been demonstrated that external vessel diameter, vessel wall thickness, and luminal area were decreased by more than 50% in patients with AD with disease duration exceeding 10 years compared with individuals diagnosed 5 years before autopsy (5). Clinically, the degree of CAA severity correlates with intracerebral hemorrhage, ischemic necrosis, and degree of dementia (6).Impaired clearance of A from the brain is thought to be one of the main causes of amyloid accumulation in sporadic AD. Several endogenous mechanisms exist for the removal of soluble A from the central nervous system (CNS) to the periphery, including receptor-mediated clearance at the BBB and via bulk movement of interstitial fluid.In addition to putative problems with receptor-mediated A transport across the BBB, it has been hypothesized that CAA might arise as a result of impaired clearance of cerebral A along perivascular spaces (7). This suggestion is supported by histological studies of AD brains that have identified A deposits in dilated perivascular spaces and within small intracortical vessels and arteries, a pattern consistent with drainage pathways nearest to the brain (7). Further, dextran and ovalbumin tracers injected into the interstitial fluid of the brain parenchyma, which distribute in patterns identical t...