Alzheimer’s disease (AD) is a degenerative brain disorder leading to dementia. Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and neuroinflammation. Studies indicate that patients with periodontitis may be at higher risk of developing AD. Our preliminary data have shown that succinate, a tricarboxylic acid cycle intermediate, significantly increased in the cerebrospinal fluid (CSF) from mice with periodontitis. Succinate can act as a signaling ligand extracellularly through succinate receptor (SUCNR1). We showed that microglial cells express SUCNR1. Interestingly, knockout (KO) of SUCNR1 significantly reduced the increases of IL1β and microglial activation induced by periodontitis in mice. The IL1β expression stimulated by administration of succinate or a key periodontal pathogen Fusobacteria nucleatum (Fn) lysate was significantly reduced in the primary microglial cells derived from KO mice. We further demonstrated that succinate can stimulated the growth and virulent gene expression of Fn and altered the oral microbiome in mice. In response to Funding Opportunity Announcement “Research on Current Topics in Alzheimer's Disease and Its Related Dementias” (PAR-22-093), we postulate that succinate elevation in periodontitis induces neurodegeneration directly via SUCNR1 activation in microglial cells, and indirectly via systemic inflammation and dysbiosis. In Aim 1 we will reveal how SUCNR1 activation in microglia modulates neuroinflammation in vitro and in vivo. Microglia are crucial for the homeostasis within the brain and our preliminary data showed that the stimulation of the nuclear factor-κB (NF-κB) pathway and IL-1β expression by succinate in microglia is SUCNR1-dependent. We will study the mechanism of microglial succinate/SUCNR1 signaling on neuroinflammation in primary microglia, littermate control (Ctrl) and microglial-specific SUCNR1 deficient (mKO) mice. In aim 2 we will assess the impact of targeting SUCNR1 on cognition impairment with chronic periodontitis. We will target SUCNR1 using mKO mice in Exp. 1 in which 20-month-old, both genders of littermate ctrl and mKO mice will be assigned randomly to have sham or chronic periodontitis for 4 months before cognition tests and sample collections. In Exp. 2 we will employ 5xFAD mice with periodontitis to determine if blocking SUCNR1 by an antagonist will alleviate periodontal bone loss, neuroinflammation and recognition deficits. The SUCNR1 antagonist treated mice and their age and gender-matched, sham/veh treated WT, and 5xFAD mice will be assessed longitudinally at 4-, 7-, and 12-month-old for neuroinflammation and cognition impairment. The proposed research will discover a novel mechanism of succinate signaling in periodontitis and AD nexus and provide a new therapeutic target for AD.