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The Journal of Neuroscience, December 24, 2008, 28(52):14156-14164; doi:10.1523/JNEUROSCI.4147-08.2008

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

Jessica Koenigsknecht-Talboo,^1,2 Melanie Meyer-Luehmann,³ Maia Parsadanian,^1,2 Monica Garcia-Alloza,³ Mary Beth Finn,^1,2 Bradley T. Hyman,³ Brian J. Bacskai,³ and David M. Holtzman^1,2

¹Department of Neurology and ²Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ³Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Correspondence should be addressed to David M. Holtzman, Washington University, Department of Neurology, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63110. Email: holtzman{at}neuro.wustl.edu

Aggregation of amyloid-β (Aβ) 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 Aβ and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-Aβ antibodies. One mechanism by which certain anti-Aβ 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-Aβ antibodies has not been fully assessed. We administered an anti-Aβ antibody (m3D6) that binds aggregated Aβ 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 Aβ. These findings demonstrate that some effects of antibodies that recognize aggregated Aβ are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD.

Key words: microglia; β-amyloid; passive immunization; Alzheimer's disease; neuritic plaques; cerebral amyloid angiopathy

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Received Aug. 30, 2008; revised Nov. 9, 2008; accepted Nov. 13, 2008.

Correspondence should be addressed to David M. Holtzman, Washington University, Department of Neurology, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63110. Email: holtzman{at}neuro.wustl.edu

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