title: APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Pankiewicz
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Jairo
authors.initials: J
authors.lastname: Baquero-Buitrago
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sanchez
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lopez-Contreras
authors.affiliation: 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.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: 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.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sadowski
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D007116:Immunization, Passive; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; C000612345:ApoE protein, human; D001057:Apolipoproteins E
keywords: Alzheimer’s disease; Apolipoprotein E; Brain hemorrhages; Microglia; Neurodegeneration; Therapy; Vasculopathy; β-amyloid