Surette, Mike, Pho, Kim, Lau, Tammy, McArthur, Andrew, Tench, Andrea, MacNeil, Lesley
[
International Worm Meeting,
2021]
Alzheimer's Disease (AD) is the most common neurodegenerative disorder, presently affecting over 46 million people worldwide. The risk of developing Alzheimer's Disease is influenced not only by genetic factors, but also by environment and lifestyle. The multi-factored pathogenesis that leads to AD development poses a challenge for identifying causal factors that promote or protect against neurodegeneration. We use Caenorhabditis elegans as a model of AD to measure the impact of human microbiota species on AD-related phenotypes. Two hallmarks of AD are amyloid-beta (Abeta) plaques and neurofibrillary tangles composed of the protein Tau. Using an Abeta-overexpressing C. elegans model, we identified several bacterial species that differentially impact paralysis, and are characterizing a group of Enterobacteriaceae species that significantly reduce paralysis. To validate these findings, we used another C. elegans model that pan-neuronally expresses Tau protein aggregates. We observed decreased neurodegeneration when the animals were exposed to most of the same bacteria protective against Abeta-induced paralysis, providing additional evidence of microbiota-promoted neuroprotection. To explore these effects, we examined global changes in gene expression in animals exposed to neuroprotective bacteria. We identified several biological processes that were differentially regulated in response to the neuroprotective microbiota species, including innate immunity and protein phosphorylation. C. elegans orthologs of human tau tubulin kinase isoforms, TTBK1 and TTBK2, were down-regulated in response to neuroprotective microbiota species. RNAi-mediated knockdown of C. elegans ttbk genes sufficiently induced neuroprotection in Tau aggregate-prone animals and decreased paralysis in Abeta-overexpressing animals. These findings suggest that bacterial species from the human microbiota can mediate neuroprotection through down-regulation of ttbk. Overall, by studying the impact of the human microbiota on models overexpressing Abeta or aggregate-prone Tau, we have uncovered a potential mechanism by which microbiota-mediated neuroprotection can occur.
Lau, Tammy, Surette, Michael G., McArthur, Andrew G., Pho, Kim, Tench, Andrea, MacNeil, Lesley T.
[
International Worm Meeting,
2019]
The risk of developing Alzheimer's Disease (AD) is influenced, not only by genetic factors, but also by environment and lifestyle. The multi-factored pathogenesis that leads to AD development poses a challenge for identifying causal factors that promote neurodegeneration. Two hallmarks of AD are amyloid-? (A?) plaques and neurofibrillary tangles composed of the protein Tau. We use Caenorhabditis elegans as a model of AD to measure the impact of human microbiota species on AD-related phenotypes. Using an A?-overexpressing C. elegans model, we identified several bacterial species that differentially impact paralysis and are characterizing a group of Enterobacteriaceae species that significantly reduce paralysis. Most of these bacteria also decreased neurodegeneration in animals that pan-neuronally express aggregate-prone Tau, providing additional evidence of microbiota-promoted neuroprotection. To explore these effects, we examined global changes in gene expression in animals exposed to neuroprotective bacteria. We identified several biological processes that are differentially regulated in response to the neuroprotective microbiota species, including innate immunity and defense response. Overall, by studying the impact of the human microbiota on models overexpressing A? or aggregate-prone Tau, we gain a greater understanding of conserved pathways involved in gene-environment interactions that influence the development of AD.