Gut-derived β-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis

Peripheral beta-amyloid (A beta), including those contained in the gut, may contribute to the formation of A beta plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived A beta in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of A beta and several key proteins involved in A beta metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of A beta was detected throughout the gut in both mice and human, and gut A beta 42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and A beta 42 levels. Intra-intestinal injection of isotope or fluorescence labeled A beta combined with vagotomy was also performed to investigate the transmission of A beta from gut to brain. The data showed that, in aged mice, the gut A beta 42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of A beta in the brain, and gut microbiota can further upregulate gut A beta production, thereby potentially contributing to AD pathogenesis.