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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

阿尔茨海默氏病（AD）是导致痴呆症的退化性脑疾病。牙周炎，一种慢性炎症性疾病，诱导全身感染和神经炎症。研究表明牙周炎患者可能患AD的风险更高。我们的初步数据已显示琥珀酸酯，三核酸循环中间体，在脑脊液中显着增加（CSF）来自牙周炎的小鼠。琥珀酸盐可以在细胞外充当信号配体琥珀酸酯受体（SUCNR1）。我们表明小胶质细胞表达SUCNR1。有趣的是， SUCNR1的基因敲除（KO）显着降低了IL1β和小胶质激活的增加小鼠牙周炎。通过琥珀酸盐或钥匙刺激的IL1β表达牙周病原体核细菌（FN）裂解物在原发性中显着降低来自KO小鼠的小胶质细胞。我们进一步证明了琥珀酸酯可以刺激生长 FN的毒性基因表达并改变了小鼠的口服微生物组。回应资金机会公告“关于阿尔茨海默氏病及其相关的当前主题的研究痴呆症”（PAR-22-093），我们假设牙周炎的琥珀酸盐升高会影响直接通过小胶质细胞中的SucNR1激活直接神经变性，并间接通过全身性炎症和营养不良。在AIM 1中，我们将揭示小胶质细胞中的SucNR1激活在体外和体内调节神经炎症。小胶质细胞对于内部稳态至关重要大脑和我们的初步数据表明，刺激核因子-κB（NF-κB）途径小胶质细胞中琥珀酸酯的IL-1β表达依赖于SucnR1。我们将研究小胶质细胞/sucnr1信号传导对原发性小胶质细胞的神经炎症，同窝窝控制（CTRL）和小胶质细胞特异性SUCNR1缺乏（MKO）小鼠。在AIM 2中，我们将评估针对慢性牙周炎的认知障碍靶向SUCNR1。我们将使用 Exp中的MKO小鼠。 1，同窝小鼠和MKO小鼠的20个月大，两性性别在认知测试前4个月随机分配为假或慢性牙周炎，并且样本收集。在Exp。 2我们将使用牙周炎的5xFAD小鼠来确定是否阻塞拮抗剂的SUCNR1将减轻牙周骨质流失，神经炎症和识别缺陷。 SUCNR1拮抗剂治疗了小鼠，他们的年龄和性别匹配的假/车辆治疗 WT和5XFAD小鼠将在4个，7个月和12个月大的神经炎症下进行纵向评估和认知障碍。拟议的研究将发现一种新颖的琥珀酸酯机制牙周炎和AD Nexus的信号传导，并为AD提供了新的治疗靶点。