PROJECT SUMMARY/ABSTRACT Increasing evidence indicates a microbial etiology of Alzheimer’s disease (AD). One of the first signs of neurodegeneration in humans is the loss of olfactory function. Importantly, the olfactory system constitutes a direct portal of entry for microorganisms into the central nervous system (CNS). Yet, the role of neuro-invasive microbes that exploit the olfactory route to cause neurodegenerative process remains unknown. Our long-term goal is to understand the role of enterobacterial infections via the olfactory route in tauopathies to develop future microbial interventions and early diagnostic tests. Shigellosis is a very common enterobacterial infection and Shigella sonnei infection is the most common cause of diarrheal disease in the US. Preliminary data indicates that S. sonnei infects the CNS of humans as well as the olfactory system and CNS of mice in models of human tauopathy. The objective of this grant is to determine how shigellosis contributes to tau pathology. The central hypothesis of this proposal is that S. sonnei can infect the nasal mucosa, penetrate the CNS and cause neurodegeneration. Our specific aims will test the following hypotheses: S. sonnei nasal infection results in cognitive impairment, tau pathology and neurodegeneration in an age-dependent manner (AIM #1); Shigella- induced neurodegeneration occurs via protein tau (AIM #2); Shigella vaccines can slow down tau pathology progression in mice (AIM #3). The proposed experiments will be performed using wild type mice as well as two different mouse models of tauopathy, the hTau mouse model (expressing all six isoforms of non-mutant human tau under the human MAPT regulatory element) and MAPT knock out mice. The significance of our proposed studies is that it will advance our understanding on how shigellosis, a very common enterobacterial pathogen in the U.S can cause neurodegeneration in the CNS. This proposal will inform aspects of microbial interventions such as vaccination to slow down neurodegeneration. Our results may also have diagnostic implications since sequencing of the nasal microbiome of tauopathy patients may become a critical early diagnostic test in the clinic.