TY - JOUR
T1 - Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
AU - McLean, John W.
AU - Bhattrai, Avnish
AU - Vitali, Francesca
AU - Raikes, Adam C.
AU - Wiegand, Jean Paul L.
AU - Brinton, Roberta Diaz
N1 - Publisher Copyright:
© 2022 McLean et al.
PY - 2022/9
Y1 - 2022/9
N2 - Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele (APOE4), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3, APOE3/4, and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4, although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.
AB - Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele (APOE4), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3, APOE3/4, and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4, although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.
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U2 - 10.1101/lm.053588.122
DO - 10.1101/lm.053588.122
M3 - Article
C2 - 36206387
AN - SCOPUS:85139571469
SN - 1072-0502
VL - 29
SP - 321
EP - 331
JO - Learning and Memory
JF - Learning and Memory
IS - 9
ER -