Translational potential of JAX hAPOE AD mouse model: Phenotypic characterization of cognitive function and amyloid beta

Abstract

AbstractBackgroundAPOEe4 is the greatest genetic risk factor for late onset Alzheimer’s Disease (LOAD). The product of this gene, apolipoprotein E isoform ε4, has been characterized as a lipid transporter and many of its receptors and mechanisms have been identified. Studies have shown that APOEe4 exacerbates accumulation of Aβ peptides and correlates with a decline in cognitive function in humans. We investigated the translational feasibility of the humanized APOE3 (JAX #029018) and APOE4 (JAX #027894) mouse model on two hallmark pathologies of LOAD: cognitive decline and b‐amyloid (Aβ) generation in brain.MethodNovel object recognition (NOR), open field (OF), and CatWalk analyses were conducted in 18 month old transgenic mice with humanized APOEe3 homozygous (B6(SJL)‐ApoEtm1.1(APOE*3)Adiuj/J), APOEe3/4, or APOEe4 homozygous genes (B6(SJL)‐ApoEtm1.1(APOE*4)Adiuj/J). NOR analyses included discrimination index, OF center zone time, whereas CatWalk included mobility measures including cadence and speed. Aβ38, Aβ40, and Aβ42 analyses were assessed in brain and plasma.ResultNo differences were detected in NOR discrimination index, NOR combined object exploration time, or OF center zone time across sex or genotype. OF mean speed was lower in APOE3/4 mice compared to APOE4 mice. Aβ38 was not detected in any group. Hippocampal Aβ42 was significantly lower in APOE3/4 mice compared to APOE4 and APOE3 mice. No differences were detected in hippocampal Aβ40 or Aβ42/40 ratios. Plasma Aβ40, Aβ42, and Aβ42/40 were lower in females relative to males. Analyses based on sex and genotype indicated that plasma Aβ40 and Aβ42 were lower in APOE3 females vs APOE3 males, and Aβ42/40 was lower in APOE3 females vs every other group.ConclusionAPOE3/4 heterozygosity may confer a protective effect against Aβ42 deposition in the hippocampus, and female APOE mice consistently exhibit lower plasma Aβ. Translational applicability to humans on measures of cognitive decline and hippocampal Aβ42 deposition at 18 months (human age equivalent ∼56 years) for APOE mice is limited.Acknowledgements: Research supported by NIA R01AG57931 and RF1AG059093