Sexual Dimorphism in the 3xTg-AD Mouse Model and Its Impact on Pre-Clinical Research

Abstract

Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism in evaluation of behavioral or molecular characteristics and outcomes. This can compromise its translation to a clinical setting. The triple-transgenic AD mouse model (3xTg-AD) is a commonly used but unique AD model because it exhibits both amyloid and tau pathology, essential features of the human AD phenotype. Mounting evidence has revealed important sexually dimorphic characteristics of this animal model that have yet to be reviewed and thus, are often overlooked in studies using the 3xTg-AD model. In this review we conduct a thorough analysis of reports of sexual dimorphism in the 3xTg-AD model including findings of molecular, behavioral, and longevity-related sex differences in original research articles through August 2020. Importantly, we find results to be inconsistent, and that strain source and differing methodologies are major contributors to lack of consensus regarding traits of each sex. We first touch on the nature of sexual dimorphism in clinical AD, followed by a brief summary of sexual dimorphism in other major AD murine models before discussing the 3xTg-AD model in depth. We conclude by offering four suggestions to help unify pre-clinical mouse model AD research inspired by the NIH expectations for considering sex as a biological variable.

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

“…Clinical studies were the first to emphasize the importance of sex-divergent patterns in AD incidence, presentation, and treatment response as critical to the mechanistic etiology of dementia. Women are disproportionately diagnosed with AD [140] and are shown to carry greater pathological burdens [141]; phenotype severity is often greater in female AD mice, including the 3xTg strain used in the current study [79,82,139,142]. In the current study, we observed notable sex differences in PERG that may be supported by sex-specific vulnerability of specific RGC populations.…”

“…The relevance of this study's sex-divergent findings on retinal function in 3xTg mice must be emphasized in light of an increasing body of research identifying sex differences in disease mechanisms among animal models of AD [139]. Clinical studies were the first to emphasize the importance of sex-divergent patterns in AD incidence, presentation, and treatment response as critical to the mechanistic etiology of dementia.…”

Sex-Related Motor Deficits in the Tau-P301L Mouse Model

“…Moreover, the lack of NFTs in Tau-P301L female mice in those regions can be also related to the lack of motor deficits. Sex dimorphism is observed in other transgenic mouse models, but the results are contradictory [ 50 ]. Therefore, more experiments are needed in order to understand these sex-related differences more precisely.…”

Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy

“…Homozygous 3xTg mice bought from Jackson Laboratory (CA, USA) were used in this study. Since previous findings suggested that male 3xTg mice may not exhibit AD-like pathology 39 , only female mice were used in our study. In 3xTg mice, celastrol was given daily from 6 months of age till the mice reached 15 months of age with concentrations of 1 and 2 mg/kg/day ( n = 8 per group).…”