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

• 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
• 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' 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

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 阿尔茨海默氏症(AD)的发病率越来越高，是一种日益严重的健康和经济危机。虽然 经过112多年的研究，散发性阿尔茨海默病的根本原因--95%的阿尔茨海默病--尚不清楚。超过了 在过去的15年里，415多项测试AD新药的临床试验失败了。批准的药物只能管理 症状。我将使用NIH先驱基金来调查一种关于散发性疾病病因的新假说 阿尔茨海默氏症，基于我的洞察力，两种天然免疫肽之间的不平衡可能 是调节AD相关纤维的形成风险、稳定性和清除的关键因素 还有斑块。慢性牙龈假单胞菌与疱疹病毒感染相关的近期观察 阿尔茨海默氏症符合这个假设。据我所知，我是唯一一个致力于这一想法的研究人员。 人类盲肠毒素LL-37是一种抗病毒和抗细菌的防御肽，在我们的蛋白质组中是独有的。 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(以杀死受感染的细胞)。 因此，LL-37是一种中枢重要的防御肽，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‘S维生素D3、RXR激动剂和丁酸依赖的表达 受感染、受伤、运动和一些疫苗(如卡介苗和口服脊髓灰质炎疫苗)的刺激。一定的 病原体，特别是牙龈假单胞菌，会释放酶毒性因子，迅速降解LL-37。 IL-37的降解可以很好地失调大脑的先天免疫，导致神经变性； 在LL-37‘S缺失的情况下，巨噬细胞自噬的免疫过程受阻。与阿尔茨海默病相关的 多肽抗体现在似乎也是一种宿主防御肽；疱疹病毒科或P。 牙龈杆菌刺激抗体的产生，使其在与病原体共存的菌斑中积累。 最近，我和他的合作者发现，IL-37和抗体都在人脑中表达，并与 彼此的序列--特别是。IL-37/Ab结合可阻止纤化并阻断Ab采用 B型二级结构。因此，LL-37的降解可能会使抗体积累。我们的活体研究 在5XFAD小鼠中诱导长春花碱可减缓AD进展并改善5XFAD认知 以匹配野生型。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 将使用野生型和盲肠毒素KO小鼠来证明牙龈假单胞菌对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，这可能是 通过早期上调长春瑞定以防止感染来预防；或口服抗菌素治疗。 我的实验室已经开发出新的抗菌剂，可以有效地杀死牙龈假单胞菌和灭活疱疹病毒。

项目成果

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

• DOI: 10.2147/ndt.s264910
• 发表时间: 2021
• 期刊: Neuropsychiatric disease and treatment
• 影响因子: 3.2
• 作者: Fulop T;Tripathi S;Rodrigues S;Desroches M;Bunt T;Eiser A;Bernier F;Beauregard PB;Barron AE;Khalil A;Plotka A;Hirokawa K;Larbi A;Bocti C;Laurent B;Frost EH;Witkowski JM
• 通讯作者: Witkowski JM

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

• DOI: 10.1186/s12979-021-00236-x
• 发表时间: 2021-06-21
• 期刊: Immunity & ageing : I & A
• 作者: Munawara U;Catanzaro M;Xu W;Tan C;Hirokawa K;Bosco N;Dumoulin D;Khalil A;Larbi A;Lévesque S;Ramassamy C;Barron AE;Cunnane S;Beauregard PB;Bellenger JP;Rodrigues S;Desroches M;Witkowski JM;Laurent B;Frost EH;Fulop T
• 通讯作者: Fulop T

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

• DOI: 10.3390/ph14040304
• 发表时间: 2021-03-31
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Diamond G;Molchanova N;Herlan C;Fortkort JA;Lin JS;Figgins E;Bopp N;Ryan LK;Chung D;Adcock RS;Sherman M;Barron AE
• 通讯作者: Barron AE

The anti-inflammatory effects of photobiomodulation are mediated by cytokines: Evidence from a mouse model of inflammation.

• DOI: 10.3389/fnins.2023.1150156
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Shamloo, Shirin;Defensor, Erwin;Ciari, Peter;Ogawa, Gaku;Vidano, Laura;Lin, Jennifer S.;Fortkort, John A.;Shamloo, Mehrdad;Barron, Annelise E.
• 通讯作者: Barron, Annelise E.

Real-Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label-Free Imaging with Optical Diffraction Tomography.

• DOI: 10.1002/advs.202302483
• 发表时间: 2023-08
• 期刊: ADVANCED SCIENCE
• 影响因子: 15.1
• 作者: Kim, Minsang;Cheon, Yeongmi;Shin, Dongmin;Choi, Jieun;Nielsen, Josefine Eilso;Jeong, Myeong Seon;Nam, Ho Yeon;Kim, Sung-Hak;Lund, Reidar;Jenssen, Havard;Barron, Annelise E.;Lee, Seongsoo;Seo, Jiwon
• 通讯作者: Seo, Jiwon