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

Issue title: Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

Guest editors: K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny and Ricardo B. Maccioni

Article type: Research Article

Authors: Cuervo-Zanatta, Daniel^{a; b} | Garcia-Mena, Jaime^{b; *} | Perez-Cruz, Claudia^{a; *}

Affiliations: [a] Pharmacology Department, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav), Laboratory of Neuroplasticity and Neurodegeneration, Mexico City, Mexico | [b] 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

Correspondence: [*] Correspondence to: Claudia Perez-Cruz, Pharmacology De-partment, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav), Laboratory of Neuro-plasticity and Neurodegeneration, Av Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360 Mexico City, CDMX, Mexico. E-mail: [email protected]. and Jaime Garcia-Mena, 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, Av Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360 Mexico City, CDMX, Mexico. E-mail: [email protected].

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.

Keywords: Anxiety, APP/PS1 mice, dysbiosis, high-throughput DNA sequencing, short-chain fatty acids, spatial memory, wildtype littermates

DOI: 10.3233/JAD-201367

Journal: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S195-S214, 2021