Microbiome Consortium: The Role of Gut Microbial Metabolism in Tau-Mediated Neurodegeneration


Alzheimer’s disease (AD) is the most common cause of dementia and a leading cause of death in the United States. It appears that the anti-amyloid antibody lecanemab can modestly slow cognitive decline in those with very mild dementia, but we need additional treatment options that attack other mechanisms. Intense efforts have sought to develop treatments that clear amyloid plaques in the brain like lecanemab, but AD also is defined by the accumulation of tangles composed of tau protein inside neurons that develop in the brain regions responsible for cognition. There is a more direct correlation between tau tangles and cognitive decline during AD, which suggests that preventing tau tangle formation will slow or prevent AD progression. Recent studies identified new genetic risk factors for AD related to immune responses, and these genes are expressed by a group of immune cells within the brain called microglia. Our research group was among the first to show that immune responses by microglia are a key contributor to neuronal loss caused by tau in animal models. These findings suggest that targeting immune responses by microglia that influence tau tangle formation and neuronal loss is a feasible AD treatment. Interestingly, bacteria that live inside the linings of the intestine are known to influence microglia function, and we recently showed that an animal model raised without gut bacteria is protected from neuronal loss caused by tau. This finding is likely because of the gut bacteria influencing immune responses by microglia. Taken together, these findings suggest that targeting gut bacteria to influence microglia function in the brain is an innovative therapeutic strategy for the tau phase of AD, but we do not have a clear understanding of how to target gut bacteria for AD treatment. Therefore, the goal of this application is to use animal models with tau pathology that develop neurodegeneration to discover new mechanisms along the “gut-brain axis” that we can target with future AD treatments. To accomplish this goal, we will first aim to understand whether the greatest AD genetic risk factor, APOE, plays a role in shaping a community of gut bacteria that influences neuronal loss. We then will determine whether one of the ways that gut bacteria communicate with microglia in the brain is through the production of metabolites that circulate in the bloodstream and bind to receptors on immune cells outside of the brain. This binding of metabolites to immune cells outside of the brain may result in signals that cross into the brain and influence microglia function in ways that lead to neuronal damage and, ultimately, loss. Finally, we will transplant gut bacteria samples from humans with AD or people without AD into our animal models to see whether the gut bacteria from a person with AD results in greater neuronal loss compared with nondiseased individuals. Completion of these studies will provide a strong scientific rationale to develop new treatments and lifestyle interventions with a novel approach of targeting the gut bacteria to treat AD. 

Funding to Date



Studies of Alternative Neurodegenerative Pathways, Translational


David Holtzman, M.D.