Alzheimer’s disease (AD) is a rapidly-growing and serious worldwide malady, which is currently the most common cause of dementia in patients of advanced age. Over several years, there have been various reports of different pathogens being detected in the brains of AD patients in post-mortem examinations. Although there is some potential controversy regarding the validity of these studies, more recent work has suggested that the amyloid (A) protein that causes brain pathology in AD patients could function as a type of host defense against microbial invaders of the brain. One of the pathogens that has been reported to be detected in the brains of AD patients is Borrelia burgdorferi (Bb), the causative agent of Lyme Disease. There are as many as 476,000 cases of Lyme disease per year in the US, posing a significant threat to public health. Importantly, a recent study by investigators who study Borrelia pathogenesis, reported that this pathogen was present in the cerebral spinal fluid of a deceased patient with Lewy Body Dementia, an AD-related dementia. However, whether a Bb infection impacts the development of AD pathology has not been investigated. In the current supplemental proposal, we will team up with Dr. Brutkiewicz, an expert in neuroimmunology, to address a putative link between a Bb infection and AD pathology. We propose to utilize the 5XFAD mouse model of AD. These mice rapidly develop A plaques which increase over time. Dr. Brutkiewicz currently has an R21 to study AD immunopathology in 5XFAD mice. In this proposed project, 5XFAD mice of different ages will be infected with Bb and given various standard cognitive assessments applicable to those given to human AD patients. In addition, we will investigate the potential roles of c-di-AMP and c-di-GMP in Bb-dependent AD pathology, as it has been well established that there are increases in the NLRP3 inflammasome in AD, and bacteria-derived c-di-AMP and c-di-GMP have shown to be potent activators of the NLRP3 inflammasome. With the current R01 support, we have developed compounds that block c-di-AMP and c-di-GMP productions in Bb. Individual groups of animals will be treated with these drugs and the brains will be temporally analyzed by MRI and then assessed for the extent of A plaque deposition, immune cell infiltration, the presence of Bb and whether this correlates with cognitive deficits. Our hypothesis is that an infection of 5XFAD mice with Bb will accelerate AD pathology and cause decreases in cognitive assessment scores as compared to age- and sex-matched wildtype mice. Furthermore, we hypothesize that the bacterial c-di-AMP and c-di-GMP pathway inhibitors will dampen the extent of Bb-induced AD development. The current R01 award focuses on elucidating the roles of c-di-AMP and c-di-GMP in Bb pathogenesis and developing compounds that inhibit the production of c-di-AMP and c-di-GMP. Thus, the proposed work in this supplemental application is within the active scope of the curre...