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：
10618888
负责人：
Annelise Emily Barron
金额：
$ 110.48万
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/10618888
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 Economics Epithelial Cells Epithelium Etiology Exercise Funding Health Herpesviridae Herpesviridae Infections Host Defense Human Immune Infection Infection prevention Knockout Mice Knowledge Life Macrophage Microglia Mus Natural Immunity Natural Killer Cells Natural regeneration Nerve Degeneration Neurons Oral Peptides Pharmaceutical Preparations Porphyromonas gingivalis Prevalence Process Production Proteome RXR Research Personnel Risk Role Structure Testing United States National Institutes of Health Up-Regulation Vaccines Viral Virulence Factors antimicrobial brain tissue cathelicidin cathelicidin antimicrobial peptide cytotoxicity improved in vivo insight 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.

项目概要/摘要阿尔茨海默氏症 (AD) 患病率的不断上升是一场日益严重的健康和经济危机。经过 112 多年的研究，散发性 AD（占 AD 的 95% 以上）的根本原因尚不清楚。过去 15 年，超过 415 项针对 AD 的新药临床试验均以失败告终。我将使用 NIH Pioneer 资助来研究散发性病因的新假设。阿尔茨海默氏痴呆症，根据我的见解，两种先天免疫肽之间的不平衡可能是调节 AD 相关原纤维形成风险、稳定性和清除的关键因素最近观察到慢性牙龈卟啉单胞菌和疱疹病毒感染相关。据我所知，阿尔茨海默氏症符合这个假设，我是唯一研究这个想法的研究人员。人类导管素 LL-37 在我们的蛋白质组中是独一无二的，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、上皮细胞、B 细胞和 NK 细胞部署（杀死受感染的细胞）。因此，LL-37 是一种至关重要的防御肽，对于杀死细菌和病毒病原体是必需的 LL-37 的维生素 D3、RXR 激动剂和丁酸盐依赖性表达也是如此。受到感染、受伤、运动和某些疫苗（例如卡介苗和 OPV 疫苗）的刺激。病原体，特别是牙龈卟啉单胞菌，会释放快速降解 LL-37 的酶毒因子。 LL-37 的降解很可能导致大脑的先天免疫失调，导致神经退行性变；如果缺乏 LL-37，阿尔茨海默病相关的巨自噬免疫过程就会受到损害。肽抗体现在似乎也是一种宿主防御肽；由疱疹病毒科或疟原虫引起的脑感染。牙龈卟啉单胞菌刺激抗体产生，导致其积聚在与病原体共处的斑块中。最近我和合作者发现LL-37和Ab都在人脑中表达，并结合 LL-37/Ab 彼此序列特异性结合可防止纤维化并阻止 Ab 采用。因此，我们的体内研究表明，LL-37 的降解可能会导致抗体积累。显示 5XFAD 小鼠中的导管素诱导可减缓 AD 进展并改善 5XFAD 认知为了匹配野生型，我的目标是将这一发现与感染相关的痴呆症联系起来。将使用野生型和抗菌素 KO 小鼠来证明 LL-37 被牙龈卟啉单胞菌降解毒力因子很可能是脑组织退化导致痴呆的原因之一，这可能是通过早期上调抗菌素来预防感染；或口服抗菌药物治疗。我的实验室开发了新的抗菌剂，可以有效杀死牙龈卟啉单胞菌并灭活疱疹病毒。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer's Disease.

针对大脑中受损的抗菌免疫来治疗阿尔茨海默病。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Fulop, Tamas;Tripathi, Shreyansh;Rodrigues, Serafim;Desroches, Mathieu;Bunt, Ton;Eiser, Arnold;Bernier, Francois;Beauregard, Pascale B;Barron, Annelise E;Khalil, Abdelouahed;Plotka, Adam;Hirokawa, Katsuiku;Larbi, Anis;Bocti, Christian;Lauren
通讯作者：
Lauren

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids.

抗菌肽对 HSV-1 和 SARS-CoV-2 具有有效的抗病毒活性。

DOI：
发表时间：
2021-03-31
期刊：
影响因子：
0
作者：
Diamond, Gill;Molchanova, Natalia;Herlan, Claudine;Fortkort, John A;Lin, Jennifer S;Figgins, Erika;Bopp, Nathen;Ryan, Lisa K;Chung, Donghoon;Adcock, Robert Scott;Sherman, Michael;Barron, Annelise E
通讯作者：
Barron, Annelise E

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.

MCI 患者中单核细胞和巨噬细胞的过度激活会导致阿尔茨海默病的进展。

DOI：
发表时间：
2021-06-21
期刊：
影响因子：
0
作者：
Munawara, Usma;Catanzaro, Michael;Xu, Weili;Tan, Crystal;Hirokawa, Katsuiku;Bosco, Nabil;Dumoulin, David;Khalil, Abdelouahed;Larbi, Anis;Lévesque, Simon;Ramassamy, Charles;Barron, Annelise E;Cunnane, Stephen;Beauregard, Pascale B;Bellenger
通讯作者：
Bellenger

Targeting Infectious Agents as a Therapeutic Strategy in Alzheimer's Disease.

针对感染因子作为阿尔茨海默病的治疗策略。

DOI：
发表时间：
2020
期刊：
影响因子：
6
作者：
Fülöp, Tamàs;Munawara, Usma;Larbi, Anis;Desroches, Mathieu;Rodrigues, Serafim;Catanzaro, Michele;Guidolin, Andrea;Khalil, Abdelouahed;Bernier, François;Barron, Annelise E;Hirokawa, Katsuiku;Beauregard, Pascale B;Dumoulin, David;Bellenger, Jea
通讯作者：
Bellenger, Jea

Antiviral effect of peptoids on hepatitis B virus infection in cell culture.

类肽对细胞培养物中乙型肝炎病毒感染的抗病毒作用。

DOI：
发表时间：
2024-03
期刊：
影响因子：
7.6
作者：
Murayama, Asako;Igarashi, Hitomi;Yamada, Norie;Aly, Hussein Hassan;Molchanova, Natalia;Lin, Jennifer S;Nishitsuji, Hironori;Shimotohno, Kunitada;Muramatsu, Masamichi;Barron, Annelise E;Kato, Takanobu
通讯作者：
Kato, Takanobu