Pharmacology Department, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav), Laboratory of Neuroplasticity and Neurodegeneration, Mexico City, Mexico.
Genetics and Molecular Biology Department, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav), Laboratory of reference and support for the characterization of genomes, transcriptomes and microbiomes, Mexico City, Mexico.
J Alzheimers Dis. 2021;82(s1):S195-S214. doi: 10.3233/JAD-201367.
Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer's disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice.
The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design.
Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences.
We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice.
This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.
正常衰老伴随着认知缺陷，影响女性和男性的认知功能。衰老时阿尔茨海默病（AD）的主要危险因素，女性患病风险更高。女性 AD 的患病率较高与绝经后突然出现的激素下降有关。然而，其他因素可能与这种与性别相关的认知能力下降有关。AD 患者和转基因（Tg）小鼠中肠道微生物群（GM）及其生物产物发生改变，直接影响雄性（M）而非雌性（F）小鼠的脑淀粉样蛋白-β病理。
本研究旨在确定 GM 组成和 M 和 F 野生型（WT）和 Tg 小鼠的认知功能障碍，采用性别/基因型分离设计。
在 6 月龄 WT 和 Tg 雄性小鼠中评估焦虑、短期工作记忆、空间学习和长期空间记忆。通过色谱法测定粪便短链脂肪酸，测序和生物信息学分析用于确定 GM 差异。
我们观察到 WT 小鼠的认知技能存在性别依赖性差异，有利于 F 小鼠。然而，雌性的认知优势在 Tg 小鼠中丧失。WT 小鼠 GM 组成中性别相关差异很少。相反，Tg-M 小鼠的肠道菌群失调比 Tg-F 小鼠更严重。Ruminococcaceae 的丰度降低与 Tg-F 小鼠的认知缺陷相关，而丁酸盐水平与 WT-F 小鼠的工作记忆和物体识别记忆更好相关。
本报告描述了 AD 小鼠模型中 GM 改变与认知障碍之间的性别依赖性关联。
