Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy.
Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta) 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 Abeta 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 Abeta(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.
Hawkes
Cheryl A
CA
Centre for Research in Neurodegenerative , University of Toronto, Toronto, Ontario, Canada M5S 3H2.
McLaurin
Joanne
J
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000098:blood supply* / Q000473:pathology*; D002686:Chitin / Q000008:administration & dosage / Q000494:pharmacology; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D008081:Liposomes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004002:Clodronic Acid; D002686:Chitin