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.

阿尔茨海默病 (AD) 是一种导致痴呆的退行性脑部疾病，这是一种慢性痴呆症。炎症性疾病，诱发全身炎症和神经炎症。我们的初步数据显示，患有牙周炎的患者患 AD 的风险可能更高。脑脊液中三羧酸循环中间体琥珀酸显着增加来自患有牙周炎的小鼠的脑脊液（CSF）可以通过细胞外充当信号配体。我们发现小胶质细胞表达 SUCNR1。 SUCNR1 的敲除（KO）显着降低了 IL1β 的增加和诱导的小胶质细胞活化注射琥珀酸或关键药物可刺激小鼠牙周炎的 IL1β 表达。牙周病原菌具核梭杆菌 (Fn) 裂解物在原代牙周中显着减少我们进一步证明琥珀酸可以刺激来自 KO 小鼠的小胶质细胞的生长。和 Fn 的有毒基因表达并改变小鼠的口腔微生物组以响应资助。机会公告“阿尔茨海默病及其相关疾病的当前课题研究” 痴呆症”（PAR-22-093），我们假设牙周炎中琥珀酸升高会诱发神经变性直接通过小胶质细胞中的 SUCNR1 激活，间接通过在目标 1 中，我们将揭示小胶质细胞中 SUCNR1 的激活方式。调节体外和体内的神经炎症对于体内的稳态至关重要。大脑和我们的初步数据表明，刺激核因子-κB (NF-κB) 通路小胶质细胞中琥珀酸的 IL-1β 表达是 SUCNR1 依赖性的，我们将研究其机制。小胶质细胞琥珀酸/SUCNR1 信号传导对原代小胶质细胞神经炎症的影响，同窝对照 (Ctrl) 和小胶质细胞特异性 SUCNR1 缺陷 (mKO) 小鼠在目标 2 中，我们将评估其影响。针对慢性牙周炎认知障碍的 SUCNR1 我们将使用 SUCNR1 为目标。实验 1 中的 mKO 小鼠，其中 20 个月大的同窝 ctrl 和 mKO 小鼠的性别在认知测试前 4 个月被随机分配患有假牙周炎或慢性牙周炎，在实验 2 中，我们将使用患有牙周炎的 5xFAD 小鼠来确定是否阻塞。 SUCNR1 拮抗剂将减轻牙周骨质流失、神经炎症和识别 SUCNR1拮抗剂治疗的小鼠及其年龄和性别匹配的假手术/对照组治疗。将在 4、7 和 12 个月大时纵向评估 WT 和 5xFAD 小鼠的神经炎症拟议的研究将发现琥珀酸的一种新机制。牙周炎和 AD 关系中的信号传导，并为 AD 提供新的治疗靶点。