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Published on: June 1, 2016
Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice
Jessica Koenigsknecht-Talboo1, Melanie Meyer-Luehmann, Maia Parsadanian
1Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
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.
Insights
Anti-amyloid-beta (Abeta) antibodies rapidly activate brain microglia in Alzheimer's disease models. This microglial response, crucial for passive immunotherapy, depends on the antibody's Fc domain and targets aggregated Abeta.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) plaque aggregation in the brain.
- Microglial cells, the brain's immune cells, surround Abeta and are implicated in AD pathogenesis.
- Anti-Abeta antibodies are a potential AD therapy, possibly working through microglial activation.
Purpose of the Study:
- To assess if and how systemic anti-Abeta antibodies activate microglia in vivo.
- To investigate the mechanism of action for passive immunotherapy targeting aggregated Abeta.
Main Methods:
- Systemic administration of an anti-aggregated Abeta antibody (m3D6) to PDAPP mice (an AD model) with fluorescent microglia.
- In vivo multiphoton microscopy to visualize microglial changes.
- Comparison with an antibody targeting soluble Abeta and Fc-domain deficient antibody.
Main Results:
- Rapid, significant increase in microglial number and process complexity observed within three days post-administration.
- Microglial activation was dependent on the Fc domain of the m3D6 antibody.
- No microglial changes were observed with an antibody targeting soluble Abeta.
Conclusions:
- Systemic administration of anti-aggregated Abeta antibodies rapidly activates microglia in an AD mouse model.
- This microglial response is Fc-dependent and specific to antibodies targeting aggregated Abeta.
- Findings provide mechanistic insight into passive immunotherapy for Alzheimer's disease.
