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.
