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

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.MethodsAPPSW/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.ResultsAnti-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0156-1) contains supplementary material, which is available to authorized users.

Immune Signaling in Neurodegeneration

“…Some AD immunotherapies have been found to be dependent on standard Fc receptor-based mechanisms (Bard et al, 2000;Koenigsknecht-Talboo et al, 2008;Liao et al, 2018), whereas other AD immunotherapies have shown ability to clear their protein targets independent of the Fc receptor (Bacskai et al, 2002;Das et al, 2003;Lee et al, 2016). Furthermore, both ApoE isoform and TREM2 function have been found to modulate the efficacy of anti-amyloid immunotherapy (Pankiewicz et al, 2017;Xiang et al, 2016). These results likely mean that a combination of both the correct protein target (or correct conformation of the protein), along with optimization of other properties of the antibody, are required both for the correct signaling pathways to be activated and the therapy to be truly effective.…”

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

“…APOE isoform-dependent effect on Aβ accumulation in APP/PS1/EKI mice While APOE may influence AD pathogenesis in several ways, one of the major mechanisms is via its effect on Aβ accumulation in the brain, specifically on Aβ seeding and clearance. As previous APOE knock-in mice have been shown to influence Aβ deposition in an isoformdependent fashion [5,6,8,9,43,56,57], we wanted to assess the effects of the major human APOE isoforms in the new APOE-KI model. Specifically, we investigated the effect of different human APOE alleles on Aβ accumulation in APP/PS1-21 transgenic mice.…”

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

“…Since presence of the e4 allele is thought to reduce Aβ clearance, this underscores the importance of immune clearance of toxic proteins from the brain in preventing AD symptoms. In fact, APOE alleles have been found to impact the efficacy of passive anti-Aβ immunization suggesting that the different alleles effect microglia's phagocytic ability for Aβ (Pankiewicz et al, 2017). -Kopec et al, 2009) rs679515, rs3818361…”