焦虑作为AD早期的危险因素在APP V717I转基因小鼠中存在性别差异

Anxiety is a Risk Factor of AD at an Early Stage With Gender Differences in APP V717I Transgenic Mice

目的阿尔茨海默病(AD)是最常见的老年痴呆症。年龄和性别是AD发病过程中最重要的两个因素。随着年龄的增长,临床前和临床症状相继出现,而焦虑是AD发展过程中典型的早期症状之一。此外,AD在女性中的发病率高于男性。然而,尽管在AD患者发病中观察到了这些差异,但仍然缺少对动物模型的评价。方法本文选择APP London突变(Val717Ile)AD转基因小鼠为研究对象。该突变是APP中最早描述的突变之一,与AD的早期发病有关。为了探究APP V717I小鼠在AD进展过程中是否存在性别差异,本文利用旷场试验、跳台试验、Morris水迷宫等动物行为试验对非认知症状和认知症状进行了评价。结果本研究发现,雌性转基因小鼠在6月龄时表现出明显的焦虑,而雄性转基因小鼠仅在10月龄时表现出焦虑。在6月龄时,雄性和雌性转基因小鼠都没有表现出认知缺陷;但是,在10月龄时,两种性别都表现出明显的认知障碍。结论这些结果表明,APP V717I Tg小鼠在记忆障碍发生前表现出焦虑样活动;在AD发展过程中,APP V717I转基因小鼠在年龄和性别上有明显的差异。本研究为AD发病过程中的年龄和性别差异提供了有利的证据。该小鼠模型也有望成为AD药物研究的必备工具,助力精准医学和区分药物使用中的性别差异。

Objective Alzheimer’s disease(AD)is the most common form of dementia.There are two main risk factors for developing AD—age and gender.By aging,preclinical and clinical symptoms are emerging in succession.Anxiety is one of the typical early symptoms during AD processing.Besides,the incidence of AD is higher in women than in men.However,although the differences were observed in the AD cohort,there is a lack of the assessment of AD experimental animal models within age and gender.Methods We choose the APP London mutation(Val717Ile)transgenic(Tg)mice for study.This is one of the first described mutations in APP,with the early onset of AD.To illustrate if the gender difference occurred in APP V717I mice during AD processing,we made use of animal behavior tests,such as open field test,step-down test and Morris water maze to evaluate the noncognitive symptom and cognitive symptom.Results In this study,we found that at 6-month age,female Tg mice showed significant anxiety,while male Tg mice only showed anxiety at 10-month age.At 6-month age,both male and female Tg mice did not show cognitive deficits;but,at 10-month age,both genders showed significant cognitive impairments.Conclusion These results indicated that APP V717I Tg mice showed anxiety-like activity before the occurrence of memory deficits;in the process of AD,APP V717I Tg mice have a clear difference in age and gender.This study provides favorable evidence for age and gender differences in the process of AD.The mouse model is also expected to become an essential tool for AD drug research,aiming to help precision medicine and distinguish gender differences in drug use.