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

作者：Pankiewicz Joanna E; Baquero Buitrago Jairo; Sanchez Sandrine; Lopez Contreras Jennifer; Kim Jungsu; Sullivan Patrick M; Holtzman David M; Sadowski Martin J^*

来源：Molecular Neurodegeneration, 2017, 12(1): 12.

DOI：10.1186/s13024-017-0156-1

• Alzheimer's disease
• Apolipoprotein E
• beta-amyloid
• Brain hemorrhages
• Microglia
• Neurodegeneration
• Therapy
• Vasculopathy

Background: APOE genotype is the foremost genetic factor modulating beta-amyloid (A beta) deposition and risk of sporadic Alzheimer's disease (AD). Here we investigated how APOE genotype influences response to anti-A beta immunotherapy.
Methods: APP(SW)/PS1(dE9) (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-A beta or TY11-15 isotype control antibodies between the ages of 12 and 15 months.
Results: Anti-A beta immunization decreased both the load of fibrillar plaques and the load of A beta immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal A beta plaque load was comparable across all APOE genotypes, APP/epsilon 4 mice showed the greatest reduction in the absolute A beta 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/epsilon 4 mice implying association between the epsilon 4 allele and impaired A beta phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular A beta (VA beta) and ubiquitously present in control mice of all APOE genotypes, although in APP/epsilon 3 mice their incidence was the lowest. Anti-A beta immunization significantly reduced VA beta burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/epsilon 2 and APP/epsilon 3 mice, respectively.
Conclusions: Our studies indicate that APOE genotype differentially modulates microglia activation and A beta plaque load reduction during anti-Aa immunotherapy. The APOE epsilon 3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE epsilon 2 allele increases risk thereof.

• 出版日期2017-1-31