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<p>Gut microbiome is emerging as silent driver in ageing and Alzheimer’s disease (AD). In AD, aggregation of protein Amyloid-β (Aβ) results in the formation of plaques in extra-neuronal spaces. Infectious bacteria in the gut also make similar amyloid plaques to support their biofilms. These microbial amyloids are abundant in the gut of Alzheimer’s and Parkinson’s disease patients, can access the brain through gut-brain axis, and exacerbate the neurodegeneration pathology. However, in the context of gut-brain axis, the interaction of microbial amyloids with immune cells and how this shape the inflammatory response, is unknown. Here, we report that mixed-species bacterial amyloids of FapC (fimbriae) and CsgA (curli) from gut pathogens <i>Pseudomonas aeruginosa</i> and <i>Escherichia coli</i> can sensitize microglia and enhance their inflammatory response against Aβ plaques. Microglia exposed to bacterial amyloids, phagocytose Aβ fibrils and cluster them together with bacterial amyloids in their phagosomes. This promotes a pro-inflammatory phenotype in microglia with the formation of ASC specs and a proteomics profile associated with neuroinflammation. The indigestible clusters develop a pro-inflammatory interactome that is secreted, inducing progressive degeneration in bystander neurons and cognitive decline as corroborated through human primary microglia, stem-cells derived brain organoids and in vivo with zebrafish AD models. These findings suggest that bacterial amyloids from gut-pathogens can play a role in progressive neurodegeneration pathologies through gut-immune-brain axis.</p>

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Gut-bacterial amyloids can prime microglia against endogenous Amyloid-β and mediate neuroinflammation in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Helen Forgham,
  • Eduardo A. Albornoz,
  • Giovanni Pietrogrande,
  • Muhammad Usman Munir,
  • Jiayuan Zhu,
  • Muhammad Awais Anjum,
  • Ka Hang Karen Chung,
  • Muhammad S. Tahir,
  • Syed Aoun Ali,
  • Aleksandr Kakinen,
  • Ernst J. Wolvetang,
  • Trent M. Woodruff,
  • Julio Aguado,
  • Daniel E. Otzen,
  • Thomas P. Davis,
  • Ibrahim Javed

摘要

Gut microbiome is emerging as silent driver in ageing and Alzheimer’s disease (AD). In AD, aggregation of protein Amyloid-β (Aβ) results in the formation of plaques in extra-neuronal spaces. Infectious bacteria in the gut also make similar amyloid plaques to support their biofilms. These microbial amyloids are abundant in the gut of Alzheimer’s and Parkinson’s disease patients, can access the brain through gut-brain axis, and exacerbate the neurodegeneration pathology. However, in the context of gut-brain axis, the interaction of microbial amyloids with immune cells and how this shape the inflammatory response, is unknown. Here, we report that mixed-species bacterial amyloids of FapC (fimbriae) and CsgA (curli) from gut pathogens Pseudomonas aeruginosa and Escherichia coli can sensitize microglia and enhance their inflammatory response against Aβ plaques. Microglia exposed to bacterial amyloids, phagocytose Aβ fibrils and cluster them together with bacterial amyloids in their phagosomes. This promotes a pro-inflammatory phenotype in microglia with the formation of ASC specs and a proteomics profile associated with neuroinflammation. The indigestible clusters develop a pro-inflammatory interactome that is secreted, inducing progressive degeneration in bystander neurons and cognitive decline as corroborated through human primary microglia, stem-cells derived brain organoids and in vivo with zebrafish AD models. These findings suggest that bacterial amyloids from gut-pathogens can play a role in progressive neurodegeneration pathologies through gut-immune-brain axis.