Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-Aβ Antibody Administration in PDAPP Mice

Aggregation of amyloid-beta (A beta) peptide in the brain in the form of neuritic plaques and cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD). Microglial cells surround aggregated A beta and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-A beta antibodies. One mechanism by which certain anti-A beta antibodies have been proposed to exert their effects is via antibody-mediated microglial activation. Whether, when, or to what extent microglial activation occurs after systemic administration of anti-A beta antibodies has not been fully assessed. We administered an anti-A beta antibody (m3D6) that binds aggregated A beta to PDAPP mice, an AD mouse model that was bred to contain fluorescent microglia. Three days after systemic administration of m3D6, there was a marked increase in both the number of microglial cells and processes per cell visualized in vivo by multiphoton microscopy. These changes required the Fc domain of m3D6 and were not observed with an antibody specific to soluble A beta. These findings demonstrate that some effects of antibodies that recognize aggregated A beta are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD.