Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model
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Abstract
Background: The prevalence of Alzheimer’s disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compare both sex- and genotype-dependent differences. Methods: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting. Results: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with subtle deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.
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The 5xFAD mouse model has been reported to exhibit sex-specific differences in phenotype.
“As the 5xFAD mouse model has been reported to exhibit sex-specific differences in phenotype, data separated by sex of significant differences are included in Supp. Figure 3, 4i-x, 6 g-l [25, 49].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [49]
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- Authors
- Sil, A., Erfani, A., Lamb, N., Copland, R., Riedel, G., & Platt, B.
- Affiliations
- University of Aberdeen (GB)
- Corresponding author
- Platt, Bettina
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2022-01-18
- Volume
- 85
- Issue
- 2
- Pages
- 755-778
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W3213055664
- Cited by
- 109
- References
- 12
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 23 · 2023: 17 · 2022: 6
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- Funders
- European Federation of Pharmaceutical Industries and Associations
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sex differences, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Sex Characteristics, Amyloid beta-Protein Precursor, Mice, Presenilin-1, Pathology, Molecular
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