Succinate signaling in periodontitis induced neuroinflammation and dementia

阿尔茨海默病（AD）是一种导致痴呆的退行性脑疾病。牙周炎，一种慢性， 炎症性疾病引起全身性炎症和神经炎症。研究表明 牙周炎患者发生AD的风险更高。我们的初步数据显示 琥珀酸，一种三羧酸循环中间产物，在脑脊液中显著增加， (CSF)牙周炎的老鼠。琥珀酸盐可以作为细胞外的信号配体， 琥珀酸受体（SUCNR 1）。我们发现小胶质细胞表达SUCNR 1。有趣的是， SUCNR 1基因敲除（KO）可显著降低IL 1 β和小胶质细胞活化诱导的IL 1 β增加。 牙周炎引起的。给予琥珀酸或一种关键的 牙周病原体具核梭杆菌（Fn）裂解物显着减少，在原发性 来源于KO小鼠的小胶质细胞。我们进一步证明了琥珀酸可以刺激生长 和Fn的毒性基因表达，并改变小鼠的口腔微生物组。由于经费 机会公告“当前阿尔茨海默病及其相关主题的研究 痴呆症”（PAR-22-093），我们假设牙周炎中琥珀酸盐的升高会诱导 神经变性直接通过SUCNR 1在小胶质细胞中的激活，间接通过 全身性炎症和生态失调。在Aim 1中，我们将揭示SUCNR 1在小胶质细胞中的激活 在体外和体内调节神经炎症。小胶质细胞对于体内的稳态至关重要， 我们的初步数据表明，核因子-κB（NF-κB）通路的刺激 小胶质细胞中琥珀酸表达IL-1β是SUCNR 1依赖性的。我们将研究 小胶质细胞琥珀酸/SUCNR 1信号传导对原发性小胶质细胞中神经炎症的影响，同窝对照 （对照）和小胶质细胞特异性SUCNR 1缺陷（mKO）小鼠。在目标2中，我们将评估 靶向SUCNR 1对慢性牙周炎认知障碍的影响我们将使用以下方法瞄准SUCNR 1： 实验中的mKO小鼠其中20个月龄的同窝出生的雌性和雄性cnc小鼠和mKO小鼠将被 在认知测试前随机分配4个月的假牙周炎或慢性牙周炎， 样品收集。在Exp. 2我们将使用患有牙周炎的5xFAD小鼠来确定是否阻断 SUCNR 1拮抗剂可减轻牙周骨丢失、神经炎症和识别 赤字SUCNR 1拮抗剂处理的小鼠及其年龄和性别匹配的假手术/溶媒处理的小鼠 WT和5xFAD小鼠将在4月龄、7月龄和12月龄时纵向评估神经炎症 和认知障碍。这项研究将发现琥珀酸的新机制 研究牙周炎与AD的关系，为AD的治疗提供新的靶点。

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.