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APOE genotype differentially modulates effects of anti-Aβ, passive immunization in APP transgenic mice

Bibliographic

Year of Publication:
2017
Contact PI Name:
Martin J. Sadowski
Contact PI Affiliation:
Department of Neurology, New York University School of Medicine, New York, New York, USA
Co-Authors:
Joanna E Pankiewicz, Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M. Sullivan, David M. Holtzman
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Janssen Alzheimer Immunotherapy
Study Goal and Principal Findings:

APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer’s disease (AD). This study investigated how APOE genotype influences response to anti-Aβ immunotherapy. APPSW/PS1dE9 (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aβ plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aβ plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aβ phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively. This study indicate that APOE genotype differentially modulates microglia activation and Aβ plaque load reduction during anti-Aβ immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
10D5 (anti-Abeta Mab)
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xApoE
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
APPxPS1xApoE
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
APPxPS1xApoE
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
Biomarkers
Dose
Formulation
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

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
Dense-core/Compact Plaques
Cerebral Amyloid Angiopathy (CAA)
Activated Microglia
Microhemorrhages
Fibrillar Plaques
beta Amyloid Load
Biochemical
Serum-Total Cholesterol
Immunochemistry
Brain-beta Amyloid Deposits
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
CD68
Hemosiderin Deposits
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Toxicology
Body Weight
General Behavior
Physical Appearance