Is the Gut a Significant Source of Amyloid-β in Alzheimer's Disease?

The early stages of Alzheimer's disease are characterized by rising levels of amyloid-β in the brain and the formation of misfolded amyloid aggregates. It is presently thought that this is a necessary precursor for the more harmful later stages of the condition, in which chronic inflammation and tau aggregation cause widespread cell death in the brain. It has been noted that amyloid-β exists outside the brain, and there is evidence for levels of amyloid-β in the vasculature to be in dynamic equilibrium with amyloid-β in the brain. Clearing amyloid-β from the bloodstream has shown some promise as an approach to reduce levels in the brain.

You may recall that the misfolded α-synuclein aggregates found in Parkinson's disease are now thought to originate in the gut in a sizable number of patients and thereafter spread to the brain. Analogously, in today's open access paper, researchers present evidence for the gut to provide a significant source of amyloid-β that is transported to the brain via the vasculature. This coincides with the evidence for Alzheimer's patients to have a significantly altered gut microbiome composition. Perhaps this affects the risk of disease via increased microbiome-spurred inflammation, but perhaps it is also generating increased amyloid-β to the point of overwhelming the clearance mechanisms in brain tissue.

In this context, it is worth noting the point that a major route of clearance of molecular waste from the brain is via drainage of cerebrospinal fluid. These drainage pathways become impaired with age, and this may also contribute to a continued imbalance in the generation and clearance of amyloid-β. Further, given that amyloid-β is an antimicrobial peptide, persistent infections may also be involved in increasing levels of amyloid-β. A tipping point exists, and multiple mechanisms may be in play to push a patient into sufficient accumulation of amyloid-β to trigger the onset of Alzheimer's pathology.

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

Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ 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 Aβ in aging, gut microbiota, and AD pathogenesis.

To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 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 Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 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 Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.

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