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Rapid microglial response around amyloid pathology following systemic anti-Aβ antibody administration in PDAPP mice


Year of Publication:
Contact PI Name:
David M. Holtzman
Contact PI Affiliation:
Washington University School of Medicine, Department of Neurology, St. Louis, Missouri, USA
Jessica Koenigsknecht-Talboo, Melanie Meyer-Luehmann, Maia Parsadanian, Monica Garcia-Alloza, Mary Beth Finn, Bradley T. Hyman, Brian J. Bacskai
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Eli Lilly and Company
Study Goal and Principal Findings:

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 following systemic administration of anti-Aβ antibodies has not been fully assessed. We administered an anti-Aβ antibody (m3D6) which binds to aggregated Aβ to PDAPP mice, an AD mouse model that was bred to contain fluorescent microglia. Three days following 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Peptide
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
beta Amyloid Deposits
Cerebral Amyloid Angiopathy (CAA)
Activated Microglia
Epidermal Growth Factor (EGF)
Chemokine C-C Motif Ligand 3/Macrophage Inflammatory Protein 1 (CCL3/MIP1)
Brain-beta Amyloid Deposits
Cerebral Amyloid Angiopathy (CAA)
Microglia Morphology
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)