Exploring the role of Imidazole Propionate on Alzheimer’s Disease and Related Dementias

Project Summary: Alzheimer's Disease (AD) and AD Related Dementias (ADRD) continue to present serious challenges in the aging population and there is a significant need to identify and reduce risk factors. A well-recognized and promising approach to reducing AD/ADRD comprises reduction of vascular injury often found to occur concomitantly with AD

pathology. Less appreciated facets of this disease include large systemic changes in physiology, including alterations in the gut microbiome that occur with age and disease. Recent studies from our group and others suggest that gut microbes play a key role in shaping vascular biology and AD pathology. Gut microbes influence

the host in part through production of metabolites that act on specific receptors expressed in distant organs, impacting multiple cellular signaling cascades, including inflammation, thrombosis, and cellular senescence. Our research group has recently identified associations between plasma levels of the gut microbiome-derived

metabolite imidazole propionate (ImP) and increased cerebrospinal fluid levels of neurofilament light chain (NfL), a biomarker of neurodegeneration. Increased ImP was also detected at higher levels in individuals with accelerated decline in performance on tests of executive function. Furthermore, we discovered that ImP impairs endothelial

cell function and disrupts the integrity of the blood-brain barrier (BBB). Validating these associations and establishing causal and mechanistic links with AD-pathology will have significant translational impact as there is a toolkit at our disposal to change the gut microbiome, including dietary changes, fecal transplants, and small

molecule inhibitors targeting the bacterial ImP production pathway, which is not present in the host. The central hypothesis of this proposal is that ImP modulates AD and ADRD progression by altering vascular endothelial function and BBB permeability. To test this hypothesis, we will characterize the relationship

between ImP, BBB disruption, and AD pathology in conventional and gnotobiotic mouse models of disease. We will also leverage existing samples and data collected among participants in the Wisconsin Alzheimer’s Disease Research Center to determine the extent to which ImP is associated with fluid AD biomarkers and vascular injury

as measured by MRI. The examination of the microbiome as a critical component that shapes AD/ADRD pathology through its effects on vascular function represents a novel perspective that we are uniquely positioned to examine.