Sexual Dimorphism in the 3xTg-AD Mouse Model and Its Impact on Pre-Clinical Research.
Sexual Dimorphism in the 3xTg-AD Mouse Model and Its Impact on Pre-Clinical Research.
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DOI：
10.3233/jad-201014
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Wahlestedt C
中科院分区：
文献类型：
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作者：
Dennison JL;Ricciardi NR;Lohse I;Volmar CH;Wahlestedt C
女性是患阿尔茨海默病 (AD) 的主要危险因素。 AD 中的性别二态性正在引起人们的关注，因为临床数据表明，女性不仅更容易患 AD，而且还会经历更严重的病理变化和更快的认知衰退。动物模型的临床前 AD 研究常常忽视在评估行为或分子特征和结果时解决性别二态性问题。这可能会影响其向临床环境的转化。三重转基因 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 表型的基本特征。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，这些特征尚未得到审查，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 模型中性别二态性的报告进行了彻底分析，包括截至 2020 年 8 月原始研究文章中分子、行为和长寿相关性别差异的发现。重要的是，我们发现结果不一致，菌株来源和不同的方法是导致对每种性别特征缺乏共识的主要原因。我们首先探讨临床 AD 中性别二态性的本质，然后简要总结其他主要 AD 小鼠模型中的性别二态性，然后深入讨论 3xTg-AD 模型。最后，我们提出了四项建议，以帮助统一临床前小鼠模型 AD 研究，其灵感来自 NIH 将性别视为生物变量的期望。
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.