Cargando…

Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease

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 validit...

Descripción completa

Detalles Bibliográficos
Autores principales: McLean, John W., Bhattrai, Avnish, Vitali, Francesca, Raikes, Adam C., Wiegand, Jean-Paul L., Brinton, Roberta Diaz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9488030/
https://www.ncbi.nlm.nih.gov/pubmed/36206387
http://dx.doi.org/10.1101/lm.053588.122
_version_ 1784792570186956800
author McLean, John W.
Bhattrai, Avnish
Vitali, Francesca
Raikes, Adam C.
Wiegand, Jean-Paul L.
Brinton, Roberta Diaz
author_facet McLean, John W.
Bhattrai, Avnish
Vitali, Francesca
Raikes, Adam C.
Wiegand, Jean-Paul L.
Brinton, Roberta Diaz
author_sort McLean, John W.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9488030
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-94880302023-09-01 Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease McLean, John W. Bhattrai, Avnish Vitali, Francesca Raikes, Adam C. Wiegand, Jean-Paul L. Brinton, Roberta Diaz Learn Mem Research 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. Cold Spring Harbor Laboratory Press 2022-09 /pmc/articles/PMC9488030/ /pubmed/36206387 http://dx.doi.org/10.1101/lm.053588.122 Text en © 2022 McLean et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first 12 months after the full-issue publication date (see http://learnmem.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research
McLean, John W.
Bhattrai, Avnish
Vitali, Francesca
Raikes, Adam C.
Wiegand, Jean-Paul L.
Brinton, Roberta Diaz
Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title_full Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title_fullStr Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title_full_unstemmed Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title_short Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
title_sort contributions of sex and genotype to exploratory behavior differences in an aged humanized apoe mouse model of late-onset alzheimer's disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9488030/
https://www.ncbi.nlm.nih.gov/pubmed/36206387
http://dx.doi.org/10.1101/lm.053588.122
work_keys_str_mv AT mcleanjohnw contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease
AT bhattraiavnish contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease
AT vitalifrancesca contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease
AT raikesadamc contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease
AT wiegandjeanpaull contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease
AT brintonrobertadiaz contributionsofsexandgenotypetoexploratorybehaviordifferencesinanagedhumanizedapoemousemodeloflateonsetalzheimersdisease