The irreversible and progressive neurodegenerative Alzheimer’s disease (AD) is characterized by cognitive decline, extracellular β-amyloid peptide accumulation, and tau neurofibrillary tangles in the cortex and hippocampus. The triple-transgenic (3xTg) mouse model of AD presents memory impairment in several behavioral paradigms and histopathological alterations from 6 to 16 months old. Additionally, it seems that dysbiotic gut microbiota is present in both mouse models and patients of AD at the cognitive symptomatic stage. The present study aimed to assess spatial learning, memory retention, and gut microbiota alterations in an early adult stage of the 3xTg-AD mice as well as to explore its sexual dimorphism. We evaluated motor activity, novel-object localization training, and retention test as well as collected fecal samples to characterize relative abundance, alpha- and beta-diversity, and linear discriminant analysis (LDA) effect size (LEfSe) analysis in gut microbiota in both female and male 3xTg-AD mice, and controls [non-transgenic mice (NoTg)], at 3 and 5 months old. We found spatial memory deficits in female and male 3xTg-AD but no alteration neither during training nor in motor activity. Importantly, already at 3 months old, we observed decreased relative abundances of Actinobacteria and TM7 in 3xTg-AD compared to NoTg mice, while the beta diversity of gut microbiota was different in female and male 3xTg-AD mice in comparison to NoTg. Our results suggest that gut microbiota modifications in 3xTg-AD mice anticipate and thus could be causally related to cognitive decline already at the early adult age of AD. We propose that microbiota alterations may be used as an early and non-invasive diagnostic biomarker of AD.

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Alzheimer’s disease (AD) is a multifactorial pathology characterized by β-amyloid (Aβ) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aβ and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aβ deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.