Investigating how microbiota affects amyloid-beta toxicity in C. elegans models

lzheimer’s disease is a progressive neurodegenerative condition and affects millions of people globally causing symptoms such as memory loss, cognitive decline, and loss of motor skills. The development of Alzheimer’s disease is linked to the deposition of amyloid beta plaques in the brain, however no effective prevention or cure exists yet. Emerging evidence suggests that microbiota may influence neurodegeneration, highlighting the potential of microbiota-based interventions, such as probiotics, in mitigating amyloid beta toxicity. However, the mechanisms contributing to this relationship are still poorly understood. This study aimed to investigate the protective effects of specific microbiota against amyloid beta toxicity using C. elegans as a model system for the development of Alzheimer’s disease therapeutics. Previous unpublished work by the Ezcurra laboratory showed Stenotrophomonas terrae (St1) and MYb57 protects against amyloid beta toxicity in GMC101 C. elegans. This study found these findings were generalisable across other strains such as C. elegans CL2006 and CL4276. To ensure there are no detrimental effects on C. elegans health by microbiota, development assays were conducted on worm length and L4 development speed when fed on different microbiota. The results showed some microbiota slightly reduced worm size and delayed L4 development, but these effects were minor and unlikely to confound aging or reproductive studies. Additionally, ~400 St1 transposon insertion mutants were generated to identify genes involved in microbial protection against Aβ toxicity, but no specific gene was isolated.

Supplementation assays using vitamin B12 and NAC were performed due to previous studies suggesting they protect against amyloid beta toxicity [1]. However, this study was unable to replicate those findings. A C. elegans strain (unc-54p::Aβ-1-42::unc-54 3'-UTR + mtl-2p::GFP; drp-1(tm1108) IV) was created to assess whether mitochondrial fission (using drp-1) is involved in the protection given by St1 and MYb57 against amyloid beta. Whilst initial results suggest drp-1 is not the pathway responsible, further validation is needed due to limited replicates. Overall, this research provides insight into the relationship between microbiota and neurodegeneration and highlights the potential of microbiota-based interventions, such as probiotics, in preventing amyloid beta toxicity. Further research of microbiota-host interactions is crucial for developing novel therapeutic strategies for Alzheimer’s disease.