APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice

Joanna E. Pankiewicz, Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M. Sullivan, David M. Holtzman, Martin J. Sadowski

Research output: Contribution to journalArticle

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Abstract

Background: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer’s disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. Methods: 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. Results: 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. Conclusions: Our studies 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.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Jan 31 2017

Fingerprint

Passive Immunization
Transgenic Mice
Genotype
Alleles
Immunotherapy
Hemosiderin
Immunization
Microglia
Blood Vessels
Apolipoproteins E
Phagocytosis
Amyloid
Alzheimer Disease
Antibodies
Incidence
Genes

Keywords

  • Alzheimer’s disease
  • Apolipoprotein E
  • Brain hemorrhages
  • Microglia
  • Neurodegeneration
  • Therapy
  • Vasculopathy
  • β-amyloid

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Pankiewicz, J. E., Baquero-Buitrago, J., Sanchez, S., Lopez-Contreras, J., Kim, J., Sullivan, P. M., ... Sadowski, M. J. (2017). APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Molecular Neurodegeneration, 12(1), 1-17. https://doi.org/10.1186/s13024-017-0156-1

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. / Pankiewicz, Joanna E.; Baquero-Buitrago, Jairo; Sanchez, Sandrine; Lopez-Contreras, Jennifer; Kim, Jungsu; Sullivan, Patrick M.; Holtzman, David M.; Sadowski, Martin J.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 31.01.2017, p. 1-17.

Research output: Contribution to journalArticle

Pankiewicz, JE, Baquero-Buitrago, J, Sanchez, S, Lopez-Contreras, J, Kim, J, Sullivan, PM, Holtzman, DM & Sadowski, MJ 2017, 'APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice', Molecular Neurodegeneration, vol. 12, no. 1, pp. 1-17. https://doi.org/10.1186/s13024-017-0156-1
Pankiewicz JE, Baquero-Buitrago J, Sanchez S, Lopez-Contreras J, Kim J, Sullivan PM et al. APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Molecular Neurodegeneration. 2017 Jan 31;12(1):1-17. https://doi.org/10.1186/s13024-017-0156-1
Pankiewicz, Joanna E. ; Baquero-Buitrago, Jairo ; Sanchez, Sandrine ; Lopez-Contreras, Jennifer ; Kim, Jungsu ; Sullivan, Patrick M. ; Holtzman, David M. ; Sadowski, Martin J. / APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1. pp. 1-17.
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AU - Kim, Jungsu

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AU - Holtzman, David M.

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