Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice.
Aggregation of amyloid-beta (Abeta) 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 Abeta and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-Abeta antibodies. One mechanism by which certain anti-Abeta 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-Abeta antibodies has not been fully assessed. We administered an anti-Abeta antibody (m3D6) that binds aggregated Abeta 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 Abeta. These findings demonstrate that some effects of antibodies that recognize aggregated Abeta are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD.
Koenigsknecht-Talboo
Jessica
J
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Meyer-Luehmann
Melanie
M
Parsadanian
Maia
M
Garcia-Alloza
Monica
M
Finn
Mary Beth
MB
Hyman
Bradley T
BT
Bacskai
Brian J
BJ
Holtzman
David M
DM
D000367:Age Factors; D000475:Alkenes; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D000682:Amyloid / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001555:Benzene Derivatives; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D016657:Cerebral Amyloid Angiopathy; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D019707:Receptors, Chemokine / Q000235:genetics; D013267:Stilbenes
C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; C491049:Aif1 protein, mouse; D000475:Alkenes; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D001555:Benzene Derivatives; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D008840:Microfilament Proteins; D019707:Receptors, Chemokine; D013267:Stilbenes; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens