Succinate signaling in periodontitis induced neuroinflammation and dementia

牙周炎引起的神经炎症和痴呆中的琥珀酸信号传导

• 批准号: 10590823
• 负责人: Xin Li
• 金额: $ 61.05万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590823
• 关键词: Acute; Age; Alveolar Bone Loss; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; Autopsy; Behavior; Blood specimen; Brain; Brain Diseases; CASP1 gene; Cell Nucleus; Cells; Cerebellum; Cerebrospinal Fluid; Chronic; Citric Acid Cycle; Cognition; Cognitive; Data; Dementia; Development; Disease; Etiology; Exhibits; Female; Formulation; Funding Opportunities; Fusobacterium nucleatum; Gel; Gender; Gene Expression; Genotype; Gingiva; Growth; Hippocampus; Histology; Homeostasis; Immunoblot Analysis; Impaired cognition; In Situ Hybridization; In Vitro; Inflammasome; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Knock-out; Knockout Mice; Ligands; Ligature; Location; Measures; Mediating; Messenger RNA; Microglia; Modeling; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Oral; Oral health; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Periodontitis; Proteins; Randomized; Receptor Activation; Receptor Signaling; Research; Rodent; Role; Serum; Signal Transduction; Succinates; Testing; Therapeutic; Tissue Banks; Tissue Sample; Virulent; Wild Type Mouse; amyloid pathology; antagonist; arm; assault; behavior test; brain tissue; cohort; cytokine; dysbiosis; extracellular; glial activation; high risk; in vivo; male; marenostrin; metagenomic sequencing; neuroinflammation; new therapeutic target; novel; novel therapeutics; object recognition; oral microbial community; oral microbiome; performance tests; periodontopathogen; receptor; receptor expression; response; sample collection; systemic inflammatory response; touchscreen; transcriptome sequencing; virulence gene

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.

阿尔茨海默病(AD)是一种导致痴呆症的退行性大脑疾病。牙周炎，一种慢性的， 炎症性疾病，导致全身炎症和神经性炎症。研究表明， 患有牙周炎的患者患AD的风险可能更高。我们的初步数据显示 琥珀酸是一种三羧酸循环中间体，在脑脊液中显著增加 (CSF)来自牙周炎小鼠。琥珀酸可通过细胞外途径作为信号配基。 琥珀酸受体(SUCNR1)。我们发现小胶质细胞表达SUCNR1。有趣的是， 基因敲除(KO)可显著降低IL-1β和小胶质细胞的激活 由小鼠牙周炎引起。琥珀酸或A键对IL-1β表达的刺激作用 牙周病原菌核梭杆菌(FN)的裂解物在初治时明显减少 KO小鼠来源的小胶质细胞。我们进一步证明了琥珀酸可以促进生长。 和FN的毒力基因表达，改变了小鼠口腔微生物群。对资金的回应 《机遇公告》阿尔茨海默病及其相关研究现状 痴呆症“(PAR-22-093)，我们假设牙周炎中琥珀酸升高会导致 在小胶质细胞中，神经退行性变直接通过SUCNR1激活，间接通过 全身性炎症和生物失调。在目标1中，我们将揭示SUCNR1在小胶质细胞中的激活 在体外和体内调节神经炎症。小胶质细胞对体内的动态平衡至关重要。 而我们的初步数据显示，核因子-κB(NF-κB)通路的刺激 琥珀酸对小胶质细胞IL-1β的表达具有依赖性。我们将研究其作用机制。 小胶质细胞琥珀酸/SUCNR1信号转导在原代小胶质细胞神经炎症中的作用 (Ctrl)和小胶质细胞特异性的SUCNR1缺陷(MKO)小鼠。在目标2中，我们将评估 靶向SUCNR1治疗慢性牙周炎认知障碍我们将使用以下工具瞄准SUCNR1 实验中的MKO小鼠其中，20个月大的Ctrl和MKO小鼠，无论男女都将是 随机分配到假牙周炎或慢性牙周炎4个月前进行认知测试和 样本集合。在实验中我们将使用5xFAD患牙周炎的小鼠来确定阻滞剂 一种拮抗剂可减轻牙周骨丢失、神经炎症和认知功能 赤字。SUCNR1拮抗剂处理的小鼠及其年龄和性别匹配的假/VEH处理 WT和5xFAD小鼠将在4个月、7个月和12个月大时进行神经炎症纵向评估 和认知障碍。这项拟议的研究将发现琥珀酸酯的一种新的作用机理 在牙周炎和AD联系中的信号转导，为AD的治疗提供了新的靶点。