Immunotherapies Targeting the Microbiota to Prevent Cognitive Decline in Alzheimer’s Disease

2022

There have been numerous associations of the composition of the microbes in the gastrointestinal (GI) tract with the occurrence of Alzheimer’s disease (AD), but how these microbes lead to changes in the brain and the associated signs and symptoms of AD are poorly understood. We have proposed that small fragments of the microbes continually break off from the cells residing on the GI tract and enter the blood or lymphatic circulation, and then can cross into the brain and lodge there. Throughout most human lives, this process is controlled in a manner that prevents any harm coming to the brain or other tissues where fragments might lodge, because they are prevented from reaching these distant tissues or cleared once lodged there. But when the factors leading to AD are present such as age, genes, diet, environment, smoking, etc., the fragments are not as easily prevented from reaching the brain or readily cleared from the brain, and therefore stay lodged there, where they become factors in the inflammatory process leading to the destruction of brain cells and tissues. We have found that many microbes have a conserved factor on their surface, a polysaccharide or sugar coating, chemically related to that of invertebrate shells such as shrimp or crab shells. This factor is called PNAG. We have developed PNAG into a vaccine that causes antibodies to be produced that we believe prevent these microbial fragments from getting to the brain, and also may promote clearance of microbial fragments if already in the brain. This should prevent destruction of brain cells and tissues. In our studies, we have used one of the mouse models of AD to test this by immunizing the mice and following the course of development of signs of AD. Our studies are still in the early stages, but we are very encouraged that AD mice that have received the PNAG vaccine are doing better in many measures compared with the AD mice that received a control vaccine. And in some of the measures, the PNAG-immune AD mice look like unaffected mice lacking any genes to cause an AD-type of disease. These studies will continue into the fall of 2022, and a second study testing passive therapy with a monoclonal antibody to PNAG will also commence in AD mice at that time.

2021

The scope of our project is based on the potential role of infectious agents in the cognitive decline of Alzheimer’s disease (AD). We hypothesize that microbial cells and fragments emanating from our normal microbiota gain access to neural tissues over time and promote inflammation, leading to loss of brain tissue integrity. Our approach will be to investigate whether vaccination against a highly conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG), will impact the neurodegenerative decline in an aggressive mouse model of AD. We also will determine whether PNAG is associated with the brain pathology in this mouse model of AD. Success will support human trials of a vaccine or anti-body to PNAG, in an appropriate clinical setting, to halt cognitive decline.