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

ABSTRACT

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.

KEYWORDS:

• β-amyloid
• gut microbiota
• gut–brain axis
• Alzheimer’s disease
• aging
• cognition

List of abbreviations

Aβ: β-amyloid; AD: Alzheimer’s disease; WT: wild type; APP/PS1: amyloid precursor protein/presenilin 1; FMT: fecal microbiota transplantation; NFTs: neurofibrillary tangles; APP: amyloid precursor protein; BACE1: β-secretase; PS1: Presenilin 1; PS2: Presenilin 2; BBB: blood-brain barrier; GM: gut microbiota; GI: gastrointestinal.

Acknowledgments

We sincerely thank the China National Health and Disease Human Brain Tissue Resource Center for providing human tissues, and we deeply appreciate the participants for their generous donation of samples.

Authors’ contributions:

JJ, ZX, YY, and JZ contributed to the conception and design of the study; JJ, ZX, YY, LZ, CZ, XZ, YM, HZ, XL, JW, and JZ contributed to the acquisition and analysis of data; JJ, ZX, LZ, YY, and JZ contributed to drafting the text or preparing the figures. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval and consent to participate

This study involving human tissue was approved by the Institutional Review Board of First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (IIT20220143B). The post-mortem brain tissues were obtained from the China National Health and Disease Human Brain Tissue Resource Center (Hangzhou, China). All materials were collected from donors who had provided written informed consent for a brain autopsy and permitted their clinical information for research purposes. The normal human intestinal tissues adjacent to cancer were obtained from the patients in the First Affiliated Hospital of Zhejiang University School of Medicine and provided with written informed consent. All animal studies and experimental procedures were approved by the Animal Care and Use Committee of the animal facility at Zhejiang University (20221077).

Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2167172

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant 81571226, 82020108012, 82001200, and 81671187, and the Innovative Institute of Basic Medical Science of Zhejiang University. The funding body did not play a role in the design of the study and collection, analysis, interpretation of data, or in writing the manuscript