Introduction

AUTHOR=Foley Kate E. , Hewes Amanda A. , Garceau Dylan T. , Kotredes Kevin P. , Carter Gregory W. , Sasner Michael , Howell Gareth R. TITLE=The APOEε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice JOURNAL=Frontiers in Aging Neuroscience VOLUME=14 YEAR=2022 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.838436 DOI=10.3389/fnagi.2022.838436 ISSN=1663-4365 ABSTRACT=Introduction

Restrictions on existing APOE mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer’s disease (AD) and dementia, APOE^ε4, by hindering observation of a key, common genotype in humans – APOE^ε3/ε4. Human studies are typically underpowered to address APOE^ε4 allele risk as the APOE^ε4/ε4 genotype is rare, which leaves human and mouse research unsupported to evaluate the APOE^ε3/ε4 genotype on molecular and pathological risk for AD and dementia.

Methods

As a part of MODEL-AD, we created and validated new versions of humanized APOE^ε3/ε3 and APOE^ε4/ε4 mouse strains that, due to unrestricted breeding, allow for the evaluation of the APOE^ε3/ε4 genotype. As biometric measures are often translatable between mouse and human, we profiled circulating lipid concentrations. We also performed transcriptional profiling of the cerebral cortex at 2 and 4 months (mos), comparing APOE^ε3/ε4 and APOE^ε4/ε4 to the reference APOE^ε3/ε3 using linear modeling and WGCNA. Further, APOE mice were exercised and compared to litter-matched sedentary controls, to evaluate the interaction between APOE^ε4 and exercise at a young age.

Results

Expression of human APOE isoforms were confirmed in APOE^ε3/ε3, APOE^ε3/ε4 and APOE^ε4/ε4 mouse brains. At two mos, cholesterol composition was influenced by sex, but not APOE genotype. Results show that the APOE^ε3/ε4 and APOE^ε4/ε4 genotype exert differential effects on cortical gene expression. APOE^ε3/ε4 uniquely impacts ‘hormone regulation’ and ‘insulin signaling,’ terms absent in APOE^ε4/ε4 data. At four mos, cholesterol and triglyceride levels were affected by sex and activity, with only triglyceride levels influenced by APOE genotype. Linear modeling revealed APOE^ε3/ε4, but not APOE^ε4/ε4, affected ‘extracellular matrix’ and ‘blood coagulation’ related terms. We confirmed these results using WGCNA, indicating robust, yet subtle, transcriptional patterns. While there was little evidence of APOE genotype by exercise interaction on the cortical transcriptome at this young age, running was predicted to affect myelination and gliogenesis, independent of APOE genotype with few APOE genotype-specific affects identified.

Discussion

APOE^ε4 allele dosage-specific effects were observed in circulating lipid levels and cortical transcriptional profiles. Future studies are needed to establish how these data may contribute to therapeutic development in APOE^ε3/ε4 and APOE^ε4/ε4 dementia patients.