Role of Innate Immune Dysregulation in the Etiology of Dementia

项目概要/摘要 阿尔茨海默氏痴呆症（AD）的日益流行是一个日益严重的健康和经济危机。虽然 经过112年以上的研究，散发性AD（占AD的95%以上）的根本原因尚不清楚。来 在过去的15年里，有415多项针对AD的新药临床试验失败。批准的药物只能管理 症状我将使用NIH先锋基金来调查一个新的假设， 阿尔茨海默氏痴呆症，基于我的见解，两种先天免疫肽之间的不平衡可能 是调节AD相关原纤维形成、稳定性和清除风险的关键因素 和斑块。慢性牙龈卟啉单胞菌和疱疹病毒感染相关的最新观察结果 符合这个假设据我所知，我是唯一致力于这个想法的研究人员。 人cathelicidin LL-37是我们蛋白质组中唯一的一种抗病毒和抗菌防御肽 由小胶质细胞、巨噬细胞、嗜中性粒细胞、上皮细胞、B细胞和NK细胞部署（以杀死感染的细胞）。 因此，LL-37是一种重要的防御肽，是杀死细菌和病毒病原体所必需的 和被感染的宿主细胞。LL-37的维生素D3-、RXR-激动剂-和丁酸盐依赖性表达也是 受感染、创伤、运动和一些疫苗（例如，BCG和OPV疫苗）。某些 病原体，特别是牙龈卟啉单胞菌，释放快速降解LL-37的酶毒性因子。 LL-37的降解可以很好地失调大脑的天然免疫，导致神经退行性变; 在LL-37缺失的情况下，巨自噬的免疫过程被削弱。老年痴呆症相关的 肽Ab现在似乎也是宿主防御肽;疱疹病毒科或P. 牙龈炎刺激Ab产生，导致其在与病原体共定位的斑块中积累。 最近，我和合作者发现LL-37和Ab都在人脑中表达，并结合 彼此的序列特异性。LL-37/Ab结合防止了纤维化并阻止Ab通过 b型二级结构。因此，LL-37降解可允许Ab累积。我们的体内研究 显示在5XFAD小鼠中凯萨林菌素诱导减缓AD进展并改善5XFAD认知 来匹配野生型我的目标是将这一发现与感染相关的痴呆症联系起来。在这个先锋项目中，我 将使用野生型和凯萨林菌素KO小鼠来证明牙龈卟啉单胞菌对LL-37的降解 毒力因子很可能是导致痴呆的脑组织退化的原因之一， 通过早期上调凯萨林菌素以预防感染来预防;或用抗微生物剂口服治疗。 我的实验室已经开发出了新的抗菌剂，可以有效地杀死牙龈卟啉单胞菌和疱疹病毒。

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.