Tags

Type your tag names separated by a space and hit enter

APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice.
Mol Neurodegener. 2017 01 31; 12(1):12.MN

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.

Authors+Show Affiliations

Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA. Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.Department of Medicine (Geriatrics), Duke University School of Medicine, Durham, NC, 27710, USA. Durham VA Medical Center's Geriatric Research, Education, and Clinical Center, Durham, NC, 27710, USA.Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA. Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA. sadowm01@med.nyu.edu. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. sadowm01@med.nyu.edu. Department of Psychiatry, New York University School of Medicine, New York, NY, 10016, USA. sadowm01@med.nyu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28143566

Citation

Pankiewicz, Joanna E., et al. "APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice." Molecular Neurodegeneration, vol. 12, no. 1, 2017, p. 12.
Pankiewicz JE, Baquero-Buitrago J, Sanchez S, et al. APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Mol Neurodegener. 2017;12(1):12.
Pankiewicz, J. E., Baquero-Buitrago, J., Sanchez, S., Lopez-Contreras, J., Kim, J., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2017). APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Molecular Neurodegeneration, 12(1), 12. https://doi.org/10.1186/s13024-017-0156-1
Pankiewicz JE, et al. APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. Mol Neurodegener. 2017 01 31;12(1):12. PubMed PMID: 28143566.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice. AU - Pankiewicz,Joanna E, AU - Baquero-Buitrago,Jairo, AU - Sanchez,Sandrine, AU - Lopez-Contreras,Jennifer, AU - Kim,Jungsu, AU - Sullivan,Patrick M, AU - Holtzman,David M, AU - Sadowski,Martin J, Y1 - 2017/01/31/ PY - 2016/08/30/received PY - 2017/01/24/accepted PY - 2017/2/2/entrez PY - 2017/2/2/pubmed PY - 2017/11/10/medline KW - Alzheimer’s disease KW - Apolipoprotein E KW - Brain hemorrhages KW - Microglia KW - Neurodegeneration KW - Therapy KW - Vasculopathy KW - β-amyloid SP - 12 EP - 12 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 12 IS - 1 N2 - 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. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/28143566/APOE_Genotype_Differentially_Modulates_Effects_of_Anti_Aβ_Passive_Immunization_in_APP_Transgenic_Mice_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0156-1 DB - PRIME DP - Unbound Medicine ER -