Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
J Alzheimers Dis. 2021;80(1):41-52. doi: 10.3233/JAD-201014.
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.
女性性别是导致阿尔茨海默病（AD）的主要危险因素。AD 的性别二态性越来越受到关注，因为临床数据表明，女性不仅更容易患上 AD，而且病情更严重，认知能力下降更快。在评估行为或分子特征和结果时，动物模型的临床前 AD 研究往往忽略了性二态性。这可能会影响其向临床环境的转化。三转基因 AD 小鼠模型（3xTg-AD）是一种常用但独特的 AD 模型，因为它同时表现出淀粉样蛋白和 tau 病理学，这是人类 AD 表型的重要特征。越来越多的证据揭示了这种动物模型的重要性别二态性特征，但尚未得到审查，因此，在使用 3xTg-AD 模型的研究中经常被忽视。在这篇综述中，我们对 3xTg-AD 模型中的性别二态性报告进行了全面分析，包括通过 2020 年 8 月的原始研究文章中发现的分子、行为和与寿命相关的性别差异。重要的是，我们发现结果不一致，并且品系来源和不同的方法是导致缺乏共识的主要原因。我们首先讨论了临床 AD 中性别二态性的本质，然后简要总结了其他主要 AD 小鼠模型中的性别二态性，然后深入讨论了 3xTg-AD 模型。最后，我们提出了四点建议，以帮助统一受 NIH 将性别视为生物学变量的期望启发的临床前小鼠模型 AD 研究。
