Microbial Dysbiosis and Bacterial Amyloids in Alzheimer s Disease
Abstract
Head injuries and post-traumatic stress disorder sustained during military service are important risk factors for the most common neurodegenerative disease, Alzheimer’s disease (AD). As the major cause of age-related disability, the societal burden of AD has been steadily increasing over the last few decades, most likely fueled by the increased life expectancy and other undefined factors. The cause of Alzheimer’s is not known in the 99% of cases that are not caused by the inherited genes. Also, there are no effective therapies for the disorder, despite decades of clinical trials. Although a first agent thought to be disease-modifying was approved by the U.S. Food and Drug Administration (FDA) on June 7, 2021, its efficacy has not yet been demonstrated. There is an urgent need for effective therapies or preventive measures for the disease, which remains acute. There have recently been important advances in our understanding of the role of our partner organisms, the microbiota (the bacteria and other microbes that live on our body surfaces and in our intestines) in health and disease. It is now clear from the work of our laboratory as well as many others that bacterial products made in the mouth, nose, and intestines can cause the clumping (aggregation) of brain proteins found in Alzheimer’s as well as activation of the immune system. These two processes, protein aggregation and inflammation, together lead to the death of nerve cells, which causes the profound cognitive loss seen in Alzheimer’s. In this project, we will work to define most precisely the nature of bacterial contributions to the disease by studying mice that have been raised in a germ-free environment and exposing them to defined bacterial populations. This is accomplished by fecal transplantation from either AD patients or healthy persons. The animals will be tested in a rigorous manner to assess their behavioral and other impairments. This approach to understanding the initiation of AD is particularly powerful because there are many things that we can do to influence the activity of our gut bacteria, including prebiotics, probiotics, diet, and antibiotics. Inflammation, i.e., accumulation and activation of immune cells in brain is a major contributing factor to AD progression. We propose a novel approach to study both microbiome and inflammation simultaneously and thus will be able to define how one controls the other. This will also immediately open up possibilities for combining effective preventive strategies by tailoring the microbiome with inflammation-altering drugs previously approved for other diseases such as asthma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211108
Entities
People
- Haribabu Bodduluri
Organizations
- United States Army
- University of Louisville