Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease

Abstract

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

Predictive Value of Gut Microbiome for Cognitive Impairment in Patients with Hypertension

“…A previous study has hinted that GM may be associated with hypertension [32,[42][43][44]. In this study, higher abundances of TM7 and TM7-3 were found in HTNCI patients than in HTNnCI patients.…”

Aging effects on the diurnal patterns of gut microbial composition in male and female mice

“…Sex differences in gut microbial composition, abundance, and diversity have been previously demonstrated, and both mice and human studies have shown the major roles of sex hormones in these difference [ 42 - 44 ]. Importantly, it has been suggested that sex-specific gut microbiome composition contributes to the development of sex-biased autoimmune diseases, cardiovascular diseases (CVD) and AD [ 42 , 45 , 46 ]. For example, the development of autoimmunity, prevalent in females, was reduced in nonobese diabetic female mice by gut microbiota transfer from adult male mice via the increase of testosterone level [ 42 ].…”

“…For example, the development of autoimmunity, prevalent in females, was reduced in nonobese diabetic female mice by gut microbiota transfer from adult male mice via the increase of testosterone level [ 42 ]. Sex differences in the prevalence of CVD and AD have been related with the differences in branched-chain amino acids and short-chain fatty acids derived from the gut microbiome [ 45 , 46 ]. Regarding a diurnal pattern of gut microbiota between sexes, only one study analyzed fecal pellets of young adult mice sampled every 4 h for 48 h [ 16 ].…”

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Thus, APP/PS1 transgenic mice can be used to evaluate dysbiosis related to memory alterations. Cuervo-Zanatta et al (2021) found that gut microbiota alterations and cognitive impairment are sexually dissociated in APP/PS1 transgenic mice. Interestingly, alterations in the gut microbiota and its byproducts have been reported in subjects with AD and APP/PS1 transgenic mice in a sex-dependent manner, having a direct impact on brain Aβ pathology in male but not in female mice.…”