Project Summary/Abstract Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that starts with alterations in behavior or language and culminates in severe impairment of memory and cognition. While in most cases the etiology of FTD is unclear, a hexanucleotide repeat expansion in C9ORF72 is the most common inherited cause of FTD and the related motor neuron disease Amyotrophic lateral sclerosis (ALS). Incomplete penetrance of the C9ORF72 mutation in families with high prevalence of FTD/ALS indicates that either genetic or environmental factors modify disease risk. Previously we found that mice with loss of function mutations in C9orf72 experienced the neural inflammatory features of FTD and died if they were raised in environments that displayed distinct microbial communities in their gut. Sequencing of fecal matter from environments where C9orf72 mutant mice displayed divergent health outcomes allowed us to nominate 40 candidate bacterial species that were enriched in the environments where animals got sick and died. In the first Aim of this proposal, we will use our proxy macrophage cytokine release assay to determine which of these 40 candidate bacterial species activate an inflammatory response so that 2-3 bacterial strains can be nominated for functional follow-up. In the second Aim, we will transplant pro-inflammatory bacteria into germ-free C9orf72 mutant mice to identify strains that trigger neural inflammation and loss of CNS immune privilege. Our studies will help to identify environmental factors that credibly contribute to observed heterogeneity in FTD patient phenotype and clinical outcome and provide insight towards selection of dementia patients most likely to benefit from therapies that target the gut microbiome.