Role of Innate Immune Dysregulation in the Etiology of Dementia

先天免疫失调在痴呆病因学中的作用

基本信息

批准号：
10437903
负责人：
Annelise Emily Barron
金额：
$ 96.23万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437903
关键词：
Adopted Agonist Alzheimer&apos s Disease Anti-Bacterial Agents B-Lymphocytes Binding Brain Butyrates Cells Cholecalciferol Chronic Clinical Trials Cognition Complex Dementia Disease Epithelial Epithelial Cells Etiology Exercise Funding Herpesviridae Herpesviridae Infections Host Defense Human Immune Infection Infection prevention Knockout Mice Knowledge Life Microglia Mus Natural Immunity Natural Killer Cells Natural regeneration Nerve Degeneration Neurons Oral Peptides Pharmaceutical Preparations Plant Roots Porphyromonas gingivalis Prevalence Process Production Proteome RXR Research Personnel Risk Role Structure Testing United States National Institutes of Health Up-Regulation Vaccines Virulence Factors antimicrobial base brain tissue cathelicidin cytotoxicity health economics improved in vivo insight macrophage neutrophil novel novel therapeutics pathogen pathogenic bacteria pathogenic virus prevent symptom management wound

项目摘要

Project Summary/Abstract Increasing prevalence of Alzheimer’s dementia (AD) is a growing health and economic crisis. Although studied for 112+ years, the root causes for sporadic AD—which is > 95% of AD—are unclear. Over the last 15 years, 415+ clinical trials to test new drugs against AD failed. Approved drugs can only manage symptoms. I will use NIH Pioneer funding to investigate a novel hypothesis for the etiology of sporadic Alzheimer’s dementia, based on my insight that imbalance between two innate immune peptides may be a key factor that modulates the risk of formation, the stability, and clearance of AD-associated fibrils and plaques. Recent observations of chronic P. gingivalis and Herpesvirus infections being associated with Alzheimer’s fit this hypothesis. I am, to my knowledge, the only researcher working on this idea. The human cathelicidin LL-37, unique in our proteome, is an antiviral and antibacterial defense peptide deployed by microglia, macrophages, neutrophils, epithelia, B cells, and NK cells (to kill infected cells). Thus LL-37 is a centrally important defense peptide, necessary for killing bacterial and viral pathogens and infected host cells. LL-37’s Vitamin D3-, RXR-agonist-, and butyrate-dependent expression is also stimulated by infection, wounding, exercise, and some vaccines (e.g., BCG & OPV vaccines). Certain pathogens, P. gingivalis in particular, release enzymatic virulence factors that rapidly degrade LL-37. Degradation of LL-37 could well dysregulate the brain’s innate immunity, causing neurodegeneration; in LL-37’s absence, the immune process of macroautophagy is crippled. The Alzheimer’s-associated peptide Ab now seems also to be a host defense peptide; brain infections by either Herpesviridae or P. gingivalis stimulate Ab production, causing it to accumulate in plaques that co-locate with pathogens. Recently I and collaborators showed that LL-37 and Ab are both expressed in human brain, and bind each other sequence-specifically. LL-37/Ab binding prevents fibrillization and blocks Ab from adopting b-type secondary structure. Thus, LL-37 degradation may allow Ab to accumulate. Our in vivo studies show that cathelicidin induction in 5XFAD mice slows AD progression and improves 5XFAD cognition to match wild-type. I aim to tie this finding to infection-associated dementia. In this Pioneer project, I will use wild-type and cathelicidin KO mice to demonstrate that degradation of LL-37 by P. gingivalis virulence factors may well be one cause of brain tissue degradation leading to dementia, which can be prevented by early upregulation of cathelicidin to prevent infection; or treated orally with antimicrobials. My lab has developed new antimicrobials that potently kill both P. gingivalis and inactivate Herpesvirus.

项目摘要/摘要阿尔茨海默氏痴呆症（AD）的患病率不断增加，这是一种日益严重的健康和经济危机。虽然研究了112年以上的研究，零星AD的根本原因（占AD的95％> 95％）尚不清楚。在最近15年，针对AD测试新药的415多个临床试验失败了。批准的药物只能管理症状。我将使用NIH先驱资金研究零星病因的新假设基于我的见解，阿尔茨海默氏症的痴呆症可能成为调节形成风险，稳定性和与广告相关原纤维的关键因素和斑块。慢性牙龈疟原虫和疱疹病毒感染的最新观察是相关的阿尔茨海默氏症符合这一假设。据我所知，我是唯一从事这个想法的研究人员。人cathelicidin LL-37在我们的蛋白质组中是独特的，是一种抗病毒和抗菌防御肽由小胶质细胞，巨噬细胞，中性粒细胞，上皮，B细胞和NK细胞（杀死感染细胞）部署。 LL-37是一种重要的中心防御肽，对于杀死细菌和病毒病原体所必需并感染了宿主细胞。 LL-37的维生素D3-，rxr-agyist-和丁酸酯依赖性表达也是受感染，缠绕，运动和一些疫苗（例如BCG和OPV疫苗）刺激。肯定病原体，牙龈疟原虫，释放迅速降解LL-37的酶促病毒因子。 LL-37的降解很可能会使大脑的先天免疫失调，从而导致神经变性。在LL-37的缺席中，大型噬菌体的免疫过程瘫痪了。阿尔茨海默氏症相关现在，肽AB现在似乎也是宿主防御肽。疱疹病毒或P的大脑感染。牙龈刺激刺激AB的产生，导致其积聚在与病原体共同关闭的斑块中。最近，我和合作者表明，LL-37和AB都在人脑中表达，并结合彼此特定于序列。 LL-37/AB结合可防止纤维化，并阻止AB采用 B型二级结构。那就是LL-37降解可能使AB积累。我们的体内研究证明5xFAD小鼠中的cathelicidin诱导减慢了广告的进展并改善了5xFAD认知匹配野生型。我的目标是将这一发现与与感染相关的痴呆症联系起来。在这个开拓者项目中，我将使用野生型和cathelicidin KO小鼠来证明牙龈疟原虫的LL-37降解病毒因素很可能是导致痴呆症的脑组织降解的原因之一，这可能是通过早期上调cathelicidin以防止感染；或用抗菌药物口服。我的实验室开发了新的抗菌剂，这些抗菌剂可能会杀死牙龈疟原虫和灭活疱疹病毒。