Abstract
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.
Highlights
Alzheimer’s disease (AD) is an age-related and neurodegenerative disorder characterized by β-amyloid plaques and tau neurofibrillary tangle formation (Serrano-Pozo et al, 2011; Martins et al, 2018) with a progressive decline in cognitive functions (Querfurth and Laferla, 2010; Serrano-Pozo et al, 2011)
The post hoc Bonferroni test showed that exploration time was higher in familiar localization 1 (Fam 1) object in female non-transgenic mice (NoTg) than female 3xTg-AD (p = 0.001) and familiar localization 2 (Fam 2) object in female NoTg in comparison with female 3xTg-AD (p = 0.005) (Figure 3A)
These data appear to contradict the results reported by Guzmán-Ramos et al (2012), in which they found that 3xTg-AD mice show a good performance in novel-object recognition (NOR) at 5 months old; the authors concluded that these mice do not show memory alterations at an early age
Summary
Alzheimer’s disease (AD) is an age-related and neurodegenerative disorder characterized by β-amyloid plaques and tau neurofibrillary tangle formation (Serrano-Pozo et al, 2011; Martins et al, 2018) with a progressive decline in cognitive functions (Querfurth and Laferla, 2010; Serrano-Pozo et al, 2011). One model for the study of AD is the triple-transgenic mouse (3xTg-AD), which contains three mutations associated with familial AD (APP Swedish, MAPT P301L, and PSEN1 M146V mutations) In this pre-clinical model, extracellular Aβ-peptide accumulation within the hippocampus appears by 6 months old, and changes in tau occur at 12–15 months old; with hyperphosphorylated tau aggregates detected in the hippocampus (Oddo et al, 2003). In comparison to males, 3xTg-AD female mice from 6 to 14 months old display worse performance in peak interval procedure, novel-object recognition (NOR) task, spontaneous alternation task, and Morris water maze (Clinton et al, 2007; Carroll et al, 2010a; Creighton et al, 2019; Gür et al, 2019)
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