Alzheimer's disease (AD) is a type of dementia that affects memory, thinking and behavior. According to the Alzheimer's Association, an estimated 6.2 million Americans are living with this progressive neurologic disorder, and it is the sixth-leading cause of death in the U.S. Although some treatments can improve quality of life for those with AD, there is no cure.
Scientists are taking a wide range of approaches to AD research, one of which is exploring how microbes in the human digestive system may affect the brain's functioning. Studies have shown the intricate relationship between the microbiome and how it affects many vital functions in the body, but gut-associated microbial communities are not yet well understood in the context of AD. To better understand this relationship, three Northern Arizona University scientists recently launched a new multidisciplinary project to examine how gastrointestinal (GI) microbiota may contribute to neurodegeneration.
Funded through a $418,000 R21 grant from the National Institutes of Health's (NIH) National Institute on Aging, assistant professor Emily Cope, associate professor Greg Caporaso and professor Egbert Schwartz recently began working together on "Development of in vivo quantitative stable isotope probing to quantify microbiome dynamics in Alzheimer's disease." NIH R21 grants are designed to provide funding for exploratory research projects that have the potential to lead to advances in health research.
Key characteristics of AD are two abnormal structures in the brain. Beta-amyloid protein deposits, or plaques, that build up in the spaces between nerve cells, and neurofibrillary tangles, twisted fibers of tau protein that build up inside cells, are both prime suspects in damaging and killing nerve cells.
Through their research to further understand gut microbiome dynamics and their relationship to AD progression and neuroinflammation, the team will adapt quantitative stable isotope probing (qSIP), a novel technology widely used in environmental microbiome sciences. The equipment used to perform qSIP analyses has been used extensively to study soil and freshwater microbial communities. Now, the same equipment will be used to look at the growth of bacterial taxa among the GI microbiota of mice that model certain characteristics of AD.
"Our goal," Cope said, "is to use a technique that was developed in soil microbial ecology (qSIP) to understand the dynamics of the microbiome in health sciences. Previous studies of human gut microbiomes show differences in the microbes that are present in individuals with AD compared to age-matched healthy participants. Studies in mice also show that mice with certain characteristics of AD have alterations in their gut microbiome. These studies support the idea that the gut microbiome may play a role in Alzheimer's disease progression, these studies, and our prior studies, use a technique that is good at telling us which microbes are present, but cannot reveal which microbes are actively growing in an environment.
"This is why qSIP is important. We're looking for microbes that are actively growing and dividing in mice modeling some characteristics of AD compared to healthy control mice. If we can show that some bacteria are dividing faster than others when some of the features of AD arise, such as amyloid-beta plaques and tauopathy, we can ask targeted questions about whether those microbes have a role in driving or protecting from disease.
"We also want to know if this method is better at predicting amyloid-beta plaque abundance and tauopathy than standard microbiome sequencing methods. We expect that we will be able to identify rare microbes that are growing quickly in mice modeling AD that would have been missed using standard methods. If we do, we can target these microbes in future studies to determine exactly how they influence brain health."
Team will apply learnings from research on chronic rhinosinusitis, asthma and cystic fibrosis
The principal investigator on the study, Cope's expertise is in host-associated microbiome sciences. As assistant director of the Center for Applied Microbiome Science at NAU's Pathogen and Microbiome Institute (PMI), she will lead and oversee all aspects of the two-year project. This research is closely related to her work investigating the role of the microbiota in chronic rhinosinusitis (CRS), asthma and cystic fibrosis.
"My group's research is centered around the role of the microbiome in chronic and progressive disease. AD is a relatively new focus for us, and we can apply our expertise and perspectives from CRS, asthma and cystic fibrosis to AD. Specifically, we have been interested in the role that the gut microbiome plays in the health status of other organs, such as the lungs in asthma and the upper respiratory tract in CRS.
"This project is a natural extension of that line of investigation, since the gut microbiota can influence health or disease status of other organs through signaling, activating the immune response and producing molecules that can enter the bloodstream. In this project, we are looking at factors from the microbiome that can influence brain health via the gut microbiome-brain axis, which is a term used to describe how the gut microbiome can influence the brain and how the brain can influence the gut microbiome."
"We have learned so much over the past few years that we have applied to this project," said Cope. "The gut microbiome is a highly dynamic ecosystem with a lot of pressures that influence which microbes are present, active and producing molecules that communicate with the host. This is truly a team effort that requires our combined expertise to ensure a successful study."
Collaboration involves team of faculty, staff and student researchers
In this highly collaborative project, Ph.D. student Emily Borsom will lead in vivo testing along with Ph.D. student Kathryn Conn and undergraduate student Daisy Barroso.
Co-investigator Caporaso, an expert in the computational aspects of microbiome research, or microbiome bioinformatics, is director of PMI's Center for Applied Microbiome Science. He leads development of the QIIME 2 microbiome bioinformatics platform in his lab and will guide the bioinformatics and statistical analysis of microbiome sequencing data for this project. This will include overseeing the work of undergraduate Computer Science student Anthony Simard in developing new software tools to support this work as well as the work of graduate Biology students in performing the required data analysis.
"This project provides a powerful opportunity to elucidate the functional relationship between gut microorganisms and features of Alzheimer's disease," Caporaso said. "Linking gut microbiome activity through qSIP, rather than static views of microbiome composition, with host phenotype provides a way to begin moving toward a mechanistic understanding of the role of gut microbes in Alzheimer's disease. This highly multidisciplinary project therefore puts us on a very exciting pathway toward improving patient outcomes."
Co-investigator Schwartz, an expert in microbial ecology, developed quantitative stable isotope probing (qSIP) and has extensive experience applying this technology in soil microbiome science. Director of the Laboratory for Isotope, Molecular, and Ecosystem Science in NAU's Center for Ecosystem Science and Society (Ecoss), he will oversee all qSIP components of this study and the work of research technician Michaela Hayer, who will perform qSIP fractionation and analysis.
"The qSIP technology was developed at Northern Arizona University and first used to quantify the growth rates of bacteria in forest soils around Flagstaff," Schwartz said. "We are very excited to extend these techniques to the microbiomes of mice and to address important questions in medical microbiology."
Arizona Alzheimer's Consortium critical to success of team's research
Cope said, "Greg Caporaso and I were invited to join the Arizona Alzheimer's Consortium (AAC) in 2019. This statewide network of researchers, led by Dr. Eric Reiman, have been key supporters of our research, along with institutional matching funds. The goals of the AAC are to promote research toward the scientific understanding and early detection of Alzheimer's disease. This network has been critical to our success in entering the competitive field of AD research. Our results stemming from their support, which we are now preparing for publication, were the foundation of this NIH/NIA R21 award."
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