Development of a microbial-rich exposure regimen to accelerate translational research using mouse models of Alzheimer's Disease to humans.

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Project Summary Accumulating evidence over the years suggests that microbial exposure and the ensuing immune response has a large role in the incidence and progression of age-associated neurodegenerative diseases, including in Alzheimer’s Disease (AD). Yet, research on this neurodegenerative disease has primarily utilized genetic mouse models that are reared in ultra-hygienic specific pathogen free (SPF) laboratory environments. The highly sanitized SPF environment prevents inadvertent microbial exposure and reduces experimental variability. But without routine microbial stimulation, the immune system of these SPF mice remains in a predominantly naïve state comprising mostly of antigen-inexperienced immune cell populations. Importantly, these naïve cells remain sequestered in the lymphoid tissues and do not access disease-affected organs. Thus, studying animals reared in SPF conditions may mask important contributions of the immune system to neurodegenerative diseases. If true, this may be a major contributing factor to the failure of translating findings from rodents to humans, which are naturally exposed to a variety of pathogens. Dr. Beura (co-investigator in this application) has demonstrated that SPF mice co-housed with pet store mice (herein referred as “dirty” mice) not only have a higher number of immune cells in peripheral organs, as compared to SPF mice, but their immune cells also display maturation traits that are more typical of the human immune system. Based on these findings and the known role of the immune system in AD, we assessed the impact of a pathogen-rich environment on the 5XFAD mouse model of AD. We present preliminary data demonstrating that the immune system is heightened in dirty compared to SPF 5XFAD mice. Additionally, our preliminary data show increased gliosis in 6-month-old dirty compared to SPF 5XFAD mice. While these findings are promising, cohousing approaches have several shortcomings that limit its wider deployment, including variable transmission of pathogens and fighting among male mice. To overcome these limitations, we developed a new microbial exposure regimen that optimizes pathogen transmission leading to reproducible changes in the immune system of both male and female mice. In this proposal, we will use this novel regimen to define the contribution of a pathogen-rich environment and matured plus heightened immune system on AD mouse models of amyloid pathology. To establish this novel approach, we will perform experiments in two aims. First, we will determine the impact of a pathogen-rich environment on immune maturation in two mouse models of AD amyloid neuropathology, 5XFAD and APPNL-F, and a mouse model of AD tauopathy, PS19. Second, we will determine the timing and magnitude of AD pathological indices in 5XFAD, APPNL-F and PS19 mice exposed to dirty and SPF conditions. Together, the proposed experiments will provide unique insights about the underpinning of AD pathogenesis and reveal unique contributions of a microbe-rich environment and matured immune system.