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

Publication ,  Journal Article
Pankiewicz, JE; Baquero-Buitrago, J; Sanchez, S; Lopez-Contreras, J; Kim, J; Sullivan, PM; Holtzman, DM; Sadowski, MJ
Published in: Mol Neurodegener
January 31, 2017

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.

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Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

January 31, 2017

Volume

12

Issue

1

Start / End Page

12

Location

England

Related Subject Headings

  • Plaque, Amyloid
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice
  • Immunohistochemistry
  • Immunization, Passive
  • Humans
  • Genotype
  • Disease Models, Animal
  • Apolipoproteins E
 

Citation

APA
Chicago
ICMJE
MLA
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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. Mol Neurodegener, 12(1), 12. https://doi.org/10.1186/s13024-017-0156-1
Pankiewicz, Joanna E., Jairo Baquero-Buitrago, Sandrine Sanchez, Jennifer Lopez-Contreras, Jungsu Kim, Patrick M. Sullivan, David M. Holtzman, and Martin J. Sadowski. “APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice.Mol Neurodegener 12, no. 1 (January 31, 2017): 12. 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. Mol Neurodegener. 2017 Jan 31;12(1):12.
Pankiewicz, Joanna E., et al. “APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice.Mol Neurodegener, vol. 12, no. 1, Jan. 2017, p. 12. Pubmed, doi:10.1186/s13024-017-0156-1.
Pankiewicz JE, Baquero-Buitrago J, Sanchez S, Lopez-Contreras J, Kim J, Sullivan PM, Holtzman DM, Sadowski MJ. APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Mol Neurodegener. 2017 Jan 31;12(1):12.
Journal cover image

Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

January 31, 2017

Volume

12

Issue

1

Start / End Page

12

Location

England

Related Subject Headings

  • Plaque, Amyloid
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice
  • Immunohistochemistry
  • Immunization, Passive
  • Humans
  • Genotype
  • Disease Models, Animal
  • Apolipoproteins E