Spatial Memory and Gut Microbiota Alterations Are Already Present in Early Adulthood in a Pre-clinical Transgenic Model of Alzheimer’s Disease

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.

Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain

“…It has been reported that Actinobacteria was increased in interstitial cystitis/bladder pain syndrome but decreased in fibromyalgia (Braundmeier-Fleming et al, 2016 ; Minerbi et al, 2019 ). In addition, the relative abundance of Actinobacteria was increased in patients with Alzheimer's disease (AD) but decreased in triple-transgenic (3xTg) AD mouse model (Zhuang et al, 2018 ; Bello-Medina et al, 2021 ). This inconsistency may be attributed to the fact that both potential pathogens and probiotics were contained in the Actinobacteria phylum.…”

Early-Life Environment Influence on Late-Onset Alzheimer’s Disease

“…Interestingly, a high-fibre diet in mothers or offspring can restore cognitive deficits in offspring by regulating the composition of bacteria and SCFA metabolites in the long-term ( Liu et al, 2021 ). It has been suggested that early deregulation of the microbiota may participate to cognitive impairment and to the onset of later lesions in the 3xTgAD mouse model ( Bello-Medina et al, 2021 ). Interestingly, addition of bioactive food to the diet restores these effects and modulates the composition of the gut microbiota ( Syeda et al, 2018 ).…”

The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment

“…Indeed, although initially hypothesized for gastrointestinal disorders [ 102 ], gut microbiome-derived biomarkers have also been considered for psychological and neurodegenerative diseases (i.e., bipolar disorder, multiple Sclerosis, and PD), reporting powerful predictivity and differential diagnosis ability [ 103 , 104 , 105 ]. Regarding AD, promising results have recently been obtained, and Table 1 summarizes the main findings [ 72 , 73 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ] ( Table 1 ). Whilst species of Prevotella and Helicobacter have been shown to be significantly different between APP/PS1 transgenic mice and controls, Actinobacteria and TM7 phylum seem to be more accurate in diagnosing AD when using the triple transgenic mouse model [ 106 , 107 , 109 ].…”

“…Regarding AD, promising results have recently been obtained, and Table 1 summarizes the main findings [ 72 , 73 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ] ( Table 1 ). Whilst species of Prevotella and Helicobacter have been shown to be significantly different between APP/PS1 transgenic mice and controls, Actinobacteria and TM7 phylum seem to be more accurate in diagnosing AD when using the triple transgenic mouse model [ 106 , 107 , 109 ]. Changes in beta diversity and variations in circulating metabolites involved in inflammatory pathways and metabolism of nucleotides, lipids, and sugars (i.e., glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotrienes) have also been considered in the same studies, showing promising results [ 106 , 107 ].…”

“…Whilst species of Prevotella and Helicobacter have been shown to be significantly different between APP/PS1 transgenic mice and controls, Actinobacteria and TM7 phylum seem to be more accurate in diagnosing AD when using the triple transgenic mouse model [ 106 , 107 , 109 ]. Changes in beta diversity and variations in circulating metabolites involved in inflammatory pathways and metabolism of nucleotides, lipids, and sugars (i.e., glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotrienes) have also been considered in the same studies, showing promising results [ 106 , 107 ]. Remarkably, when the gut microbiota of APP/PS1 mice at different ages was compared to matched controls, huge shifts in the abundance of the families Proteobacteriaceae, Verrucomicrobiaceae, Bifidobacteriaceae, Erysipelotrichaceae, Prevotellaceae, Bacteroidaceae, and Rikenellaceae could be detected far before any plaque deposition in the brain, suggesting a great potentiality for early diagnosis [ 110 ].…”