Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

酸性神经酰胺酶活性对 MIF 介导的循环破骨细胞前体向与衰老相关的牙周骨病变迁移的影响

• 批准号: 10286664
• 负责人: Alexandru Movila
• 金额: $ 38万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286664
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Attenuated; Autopsy; Blood Circulation; Brain; Cathepsins B; Cell Membrane Permeability; Cells; Ceramides; Data; Development; Experimental Models; Female; Foundations; Human; Immune response; Impaired cognition; In Vitro; Inflammation; Inflammatory; Knock-out; Late Onset Alzheimer Disease; Lesion; Ligation; Lipids; Lipopolysaccharides; Macrophage Activation; Mediating; Memory; Microglia; Molecular; Mus; Nerve Degeneration; Neuraxis; Osteoclasts; Pathogenicity; Pathology; Patients; Peptide Hydrolases; Peptide Initiation Factors; Periodontitis; Pilot Projects; Porphyromonas gingivalis; Reporting; Research Project Grants; Risk Factors; Role; TLR2 gene; Technology; Time; Virulence Factors; Wild Type Mouse; age related; base; bone; carboxypeptidase C; dihydroceramide; galactosylgalactosylglucosylceramidase; hyperphosphorylated tau; macrophage; male; migration; mouse model; multidisciplinary; neuroinflammation; novel; novel therapeutic intervention; parent grant; periodontopathogen; prevent; sex; single-cell RNA sequencing; skills; transcriptome

ABSTRACT This application will investigate the novel pathogenic host-bacterial interactions of which microglial-associated neuroinflammatory hallmarks of Late Onset Alzheimer’s disease (LOAD) emerges with periodontitis in relation to aging. The emerging evidence indicates that ligation of lipopolysaccharide (LPS) produced by the key periodontal pathogen Porphyromonas gingivalis, with Toll-Like Receptors-2 and -4 may serve as a risk factor for the initiation and/or progression of LOAD induced in young wild type mice. However, using the active R01 parent grant, we recently demonstrated that P. gingivalis-LPS/TLRs axis is attenuated in relation to aging, suggesting that an alternative pro-inflammatory mechanism may be engaged in the age-dependent pathologies, including LOAD. Our group also found that P. gingivalis produces a novel class of a host cell-membrane permeable ceramide lipid termed phosphoglycerol dihydroceramide (PGDHC) which elevates macrophage activation independently of TLRs. Furthermore, a study demonstrated that among the virulence factors produced by P. gingivalis, only PGDHC is found abundantly in the periodontal lesions as well as in the blood circulation. In addition, our preliminary data show that PGDHC is frequentely detected in the postmortem brains of patients with Alzheimer’s disease compared to that in healthy indviduals. Other preliminary results demonstrated that PGDHC elevates periodontal inflammation by acting on lysosomal protease Cathepsin B. Furthermore, it was reported that cathepsin B exacerbated the LOAD-like neuroinflammation and neurodegeneration in a mouse model of periodontitis induced by P. gingivalis. Although studies of Alzheimer’s disease pathology have predominantly focused on the amyloid-β and hyperphosphorylated tau, recent multidisciplinary findings strongly suggest that neuroinflammation associated with aberrant immune responses of the central nervous system (CNS) resident macrophages, microglia, is the third hallmark features of LOAD. However, it remains elusive whether PGDHC can promote microglia activation leading to the LOAD neuroinflammation. Based on these lines of evidence, we hypothesize that, in the context of LOAD-associated neuroinflammation, a novel PGDHC/Cathepsin B axis is engaged in the microglial activation. In the course of this one-year pilot study, we will investigate the impact of PGDHC on the cathepsin B-dependent activation of mouse primary microglia cells in vitro as well as the LOAD-like neuroinflammation and memory skills in relation to aging using female and male Cathepsin B-knock out and their wild type mice. Then, we will employ the single cell RNA-seq technology to identify transcriptome profiles between distinct subtypes of microglia isolated from the brains of wild type mice in relation to aging and sex. The proposed research project will, for the first time, establish the possible role of P. gingivalis-derived dihydroceramides in neuroinflammation and will provide a foundation for the development of a novel therapeutic approach for preventing periodontitis-associated cognitive decline in LOAD.

摘要 本申请将研究小胶质细胞相关的新的致病性宿主-细菌相互作用， 迟发性阿尔茨海默病（LOAD）的神经炎症标志与牙周炎有关， 变老新出现的证据表明，连接脂多糖（LPS）产生的关键， 牙周病原体牙龈卟啉单胞菌，与Toll样受体-2和-4可能作为一个危险因素， 在年轻野生型小鼠中诱导的LOAD的开始和/或进展。但是，使用活动R 01父代 授予，我们最近证明，牙龈卟啉单胞菌-LPS/TLRs轴衰减与衰老有关，提示 另一种促炎机制可能参与年龄依赖性病理，包括 即可.我们的研究小组还发现，牙龈卟啉单胞菌产生一类新的宿主细胞膜渗透 一种称为磷酸甘油二氢神经酰胺（PGDHC）的神经酰胺脂质，可提高巨噬细胞活化 独立于TLR。此外，有研究表明，在P. 在牙龈炎中，只有PGDHC大量存在于牙周病变以及血液循环中。在 此外，我们的初步数据显示，PGDHC在患者死后的脑组织中频繁检测到 与健康个体相比，其他初步结果表明， PGDHC通过作用于溶酶体蛋白酶组织蛋白酶B而加重牙周炎症。而且还是 组织蛋白酶B加重了小鼠的LOAD样神经炎症和神经变性 牙龈卟啉单胞菌诱导的牙周炎模型。尽管阿尔茨海默病的病理学研究 主要集中在淀粉样蛋白-β和过度磷酸化的tau蛋白，最近的多学科研究结果强烈 提示与中枢神经系统异常免疫反应相关神经炎症 (CNS)常驻巨噬细胞，小胶质细胞，是LOAD的第三个标志性特征。然而， PGDHC是否能促进小胶质细胞活化导致LOAD神经炎症。根据这些线条 根据证据，我们假设，在负荷相关神经炎症的背景下， PGDHC/Cathepsin B轴参与小胶质细胞的活化。在为期一年的试点研究中，我们 将研究PGDHC对小鼠原代小胶质细胞组织蛋白酶B依赖性激活的影响 以及与衰老有关的LOAD样神经炎症和记忆技能， 组织蛋白酶B基因敲除小鼠及其野生型小鼠。然后，我们将采用单细胞RNA-seq技术， 鉴定从野生型小鼠脑中分离的小胶质细胞的不同亚型之间的转录组谱 与年龄和性别的关系。拟议的研究项目将首次确定 P.牙龈衍生的二氢神经酰胺在神经炎症，并将提供一个基础的发展 一种新的治疗方法，用于预防牙周炎相关的认知能力下降的负荷。