Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model

Abstract

The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer’s disease (AD). CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling spatiotemporally mediates AD pathologies in the brain via cleaving both β-amyloid precursor protein and Tau. We show that gut dysbiosis occurs in 5xFAD mice, and is associated with escalation of the C/EBPβ/AEP pathway in the gut with age. Unlike that of aged wild-type mice, the microbiota of aged 3xTg mice accelerate AD pathology in young 3xTg mice, accompanied by active C/EBPβ/AEP signaling in the brain. Antibiotic treatment diminishes this signaling and attenuates amyloidogenic processes in 5xFAD, improving cognitive functions. The prebiotic R13 inhibits this pathway and suppresses amyloid aggregates in the gut. R13-induced Lactobacillus salivarius antagonizes the C/EBPβ/AEP axis, mitigating gut leakage and oxidative stress. Our findings support the hypothesis that C/EBPβ/AEP signaling is activated by gut dysbiosis, implicated in AD pathologies in the gut.

Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice

“…To date, considerable research has been devoted to investigating the gut–brain axis, with a steadily growing appreciation of the gut microbiota, which might contribute to aging and influence CNS function in health and disease [ 70 , 71 ]. Our recent research proved that R13, a prodrug of 7,8-DHF, acted as a prebiotic in the gut and decreased gut leakage and oxidative stress in Alzheimer's disease (AD) model mice, alleviating gut dysbiosis and AD [ 71 ]. The circulating endotoxin LPS, which is derived from the release of some Gram-negative bacteria in the intestines, was notably reduced by treatment with 7,8-DHF.…”

Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

“…Previous studies have reported lower bacterial diversity and more similar bacteria composition when young AD mice are compared with wildtype counterparts [ 90 , 107 , 132 ], while further differences are shown as the age of the animals increase [ 90 ]. Following this idea, gut microbiota from young APP/PS1 mice [ 107 ] and 5xFAD mice [ 131 , 133 ] are similar to that observed in wildtype animals. No significant differences in either α- or β-diversity have been observed in 5xFAD mice at 9–10 weeks old [ 133 ], although α-diversity is lower in these mice by 6 and 12 months of age [ 134 ].…”

“…Differences in gut microbiota are observed when wildtype and AD mice are compared ( Table 1 ) [ 107 , 111 , 131 ]. Previous studies have reported lower bacterial diversity and more similar bacteria composition when young AD mice are compared with wildtype counterparts [ 90 , 107 , 132 ], while further differences are shown as the age of the animals increase [ 90 ].…”

“…On the other hand, β-diversity shows significant differences in the microbiome composition of APP/PS1 mice by 2, 6 [ 90 ] and 9 months of age [ 135 ] when compared with their wildtype counterparts. So, as disease progresses a marked temporal shift in the taxonomic distribution of principal phyla is detected, and the Firmicutes / Bacteroidetes ratio increases in APP/PS1 [ 107 ] and 5xFAD mice [ 131 , 134 ] in an age-dependent manner. An increase in Firmicutes / Bacteroidetes ratio is also observed when bacterial extracellular vesicles are analyzed in the serum of 8-month APP/PS1 mice [ 136 ].…”

Functional Amyloids Are the Rule Rather Than the Exception in Cellular Biology

“…Regarding sporadic Parkinson Disease, Braak’s hypothesis suggests that alpha-synuclein aggregation could be triggered by outside pathogens that introduce amyloids to distal nervous tissue [ 101 ]. Interestingly, several recent publications suggest that Braak’s pathogens could be bacterial amyloids from the microbiome [ 102 , 103 , 104 , 105 ]. In the case of dialysis-related amyloidosis, interventional medicine is to blame for the buildup of β2-microglobulin amyloids at needle injection sites [ 106 ].…”