Neuroscientist receives $2.32 million grant to study the role of the microbiome in Alzheimer’s disease

Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at the University of Chicago, has received a grant for $2,322,876 over three years from philanthropic foundation Good Ventures to support research on Alzheimer's disease. Good Ventures, with support from the Open Philanthropy Project, funds scientific research that might help reduce the future burden of Alzheimer's disease.

This grant, along with grants to Massachusetts General Hospital, University of Southern California, Northwestern University and Washington University, is designed to support a collaborative group of researchers that will share knowledge and scientific tools. This collaborative group will investigate the roles of the gut and brain microbiome on Alzheimer's disease and its related symptoms in humans and mice, particularly their interactions with immune cells and genes, and influence of the blood-brain barrier on these processes. Good Ventures' total support for the collaborative is $10,468,059 over three years.

“The funding from Good Ventures offers us a tremendous opportunity to extend our descriptive findings to clarify mechanisms through the use of state-of-the-art transcriptomic, proteomic, metagenomic and metabolomic strategies in our well-characterized mouse models,” Sisodia said.

Over the past two years, Sisodia and his team have been studying how the makeup of the gut microbiome might play a role in inflammation of the nervous system, which in turn influences deposits of amyloid-ß (Aß) peptides in the brain, a telltale pathological signature of Alzheimer’s disease. In a 2016 study, Sisodia, postdoctoral researcher Myles Minter, PhD, and collaborators showed how long-term treatment with broad spectrum antibiotics decreased levels of amyloid plaques and activated inflammatory microglial cells in the brains of mice.

The study also showed significant changes in the gut microbiome of these mice after antibiotic treatment, suggesting the composition and diversity of bacteria in the gut play an important role in regulating immune system activity that impacts progression of Alzheimer's disease.

In a 2017 study, they performed similar experiments, but instead of giving the mice antibiotics long-term, they did it for just one week when the mice were only two weeks old. They saw all the same changes in Aß plaques, microglial cell activity and gut bacteria diversity, although to a slightly lesser extent. This study pointed to the importance of the window during early development when the gut microbiome establishes itself and begins to regulate the immune system long-term.

Sisodia’s lab will use the new grant to continue this work to understand the exact mechanisms behind how the changes in gut microbes might be related to changes in microglial cells and their ability to clear plaques. The team will also develop genetic experiments to understand the molecular changes taking place that could affect signals between gut bacteria and the immune and nervous systems.

In a recent study, Sisodia and postdoctoral researchers Hemraj B. Dodiya and Shabana Sheikh investigated gender-specific effects of the gut microbiome on cerebral Aß amyloidosis and microglial phenotypes. “We have discovered that alterations in the microbiome only impact amyloid pathology and microglial function in males, but not females, and we feel it is essential that we clarify the underlying molecular pathways that mediate these sex-specific effects that might serve to explain the increased prevalence of Alzheimer’s disease in women,” Sisodia said. “We anticipate that our findings will provide important information pertaining to the role of the gut microbiome in the pathogenesis of Alzheimer’s disease and ultimately, lead to the identification of novel, mechanism-based therapeutic strategies.”

Good Ventures is a philanthropic foundation in San Francisco whose mission is to help humanity thrive. It was co-founded by Cari Tuna, a former Wall Street Journal reporter, and her husband Dustin Moskovitz, a co-founder of Facebook and Asana.