The gut microbiome has been implicated in numerous diseases, including Alzheimer’s disease (AD). One proposed mechanism for how changes in the gut affect the brain involves immune responses that interact with or trigger the brain’s resident immune cells (astrocytes and microglia). However, the upstream mechanisms governing this interaction remain unclear. Dr. Vassar’s project will test the broad hypothesis that the gut microbiome regulates astrocyte and microglial activation, which, in turn, alters the deposition or clearance of amyloid in the brain.
To determine whether changes in the gut microbiome trigger downstream effects in mouse models, it is common to administer a broad-spectrum antibiotic cocktail that alters the balance of microbial species. In mouse models of AD, antibiotic treatment reduced amyloid plaque deposition and restored activated microglia to their resting, surveillance state. While the effects of changes in the gut microbiome on microglial responses in AD have been more thoroughly explored than those on astrocytes, Dr. Vassar’s lab has found that short-term antibiotic treatment decreases the activation state and number of astrocytes near plaques in an amyloid mouse model. They also found that AD mice raised in a germ-free environment, which lack a gut microbiome, exhibit astrocyte states similar to those in antibiotic-treated mice. Independent work from the Holtzman lab has also shown that the gut microbiome regulates astrocytes in mouse models of tauopathy.
One of the key findings during the first Microbiome consortium funding cycle was the role of propionate, a short-chain fatty acid produced by certain gut bacteria, in reducing astrocyte-mediated inflammation and amyloid pathology. The team also found that this increase in propionate was associated with a rise in a specific bacterial species: Akkermansia. This is the same species that the Cox team identified in their studies. This finding positions the two teams to delve deeper into the mechanisms underlying the benefits of Akkermansia and propionate.
In this proposal, the Vassar team will collaborate with several other consortium teams to further their investigation. In collaboration with the Cox team, the Vassar lab will test several distinct Akkermansia strains isolated by the Cox lab to determine which strains provide the most benefit and why. In collaboration with the Holtzman team, they will seek to determine whether propionate influences immune activity through free-fatty acid receptors (FFAR2/3). Dr. Holtzman previously generated FFAR2/3 knockout mice, enabling the Vassar lab to quickly determine whether removing FFAR2/3 is sufficient to eliminate propionate’s benefits. Finally, they will investigate the role of IL-17 in triggering astrocyte-mediated inflammation. The Vassar lab previously showed that the benefits of propionate were IL-17 dependent, but little is known about IL-17’s function in astrocytes or how it influences inflammation or amyloid pathology. They will tease these mechanisms apart as part of this project.
