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Role of the MyD88-independent pathway in Alzheimers disease

MyD88 独立通路在阿尔茨海默病中的作用

基本信息

批准号：
8676620
负责人：
Ken-ichiro Fukuchi
金额：
$ 23.93万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676620
关键词：
Acute Adaptor Signaling Protein Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Proteins Amyloidosis Autoimmune Diseases Behavioral Bone Marrow Brain CD14 Antigen CD14 gene Cell Surface Receptors Cell surface Cells Cerebrum Chronic Cognitive Complement Complex Data Dementia Deposition Disease Progression Elderly Endocytosis Endosomes Etiology Event Exhibits Gene Targeting Goals Growth Factor Immune Immune response Immune system Immunotherapeutic agent Immunotherapy Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Ingestion Interferons Interleukin-1 Receptors Learning Ligands Ligation Lipopolysaccharides Malignant Neoplasms Mediating Microglia Molecular Mus Myelogenous Nerve Degeneration Neuraxis Neuronal Plasticity Pathway interactions Patients Pattern recognition receptor Phagocytes Phagocytosis Play Proteins Receptor Signaling Research Role Senile Plaques Signal Pathway Signal Transduction TLR1 gene TLR2 gene TLR3 gene TLR4 gene TLR5 gene TLR6 gene TLR7 gene TLR8 gene Testing Therapeutic Tissues Toll-like receptors Transcriptional Activation base chemokine cognitive function cytokine cytotoxic improved in vivo insight loss of function mutation monocyte mouse model mutant neuronal survival novel pathogen prevent public health relevance receptor reconstruction response therapeutic target transcription factor wasting

项目摘要

DESCRIPTION (provided by applicant): Patients with Alzheimer's disease (AD) develop deposits of abnormally aggregated amyloid ¿-protein (A¿) in neuritic plaques and cerebral vessels in the brain. Accumulation of abnormally aggregated A¿ is postulated to be the initiating event leading to neurodegeneration and dementia in AD. Therefore, therapeutic strategies that clear and/or prevent A¿ accumulation are predicted to be effective against AD. Fibrillar A¿ deposits in the AD brain are accompanied by activated microglia. Fibrillar A¿ can activate microglia through Toll-like receptors (TLRs) including TLR4. TLRs are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate monocytes/microglia in response to pathogens and damaged host cells, and to clear pathogens, damaged tissues, and accumulated wastes. Activation of microglia through TLR4 markedly boosts ingestion and/or clearance of A¿. We have shown that AD model mice homozygous for a loss-of-function mutation of TLR4 had an increase in A¿ load in the brain, compared to AD model mice with TLR4 wild-type alleles. In response to TLR4 ligands, TLR4 signals through the adaptor proteins, myeloid differentiation factor 88 (MyD88) and/or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-¿ (TRIF), MyD88-dependent and MyD88-independent/TRIF-dependent pathways, respectively. In order to determine the role of the MyD88 pathways in A¿ clearance, we have investigated the effects of MyD88 deficiency (MyD88-/-) on A¿ accumulation in an AD mouse model. MyD88 deficiency decreased cerebral A¿ load in an AD mouse model. Therefore, we hypothesize that the TLR4-mediated MyD88-dependent pathway exacerbates cerebral ¿-amyloidosis in vivo and that TLR4-mediated MyD88-independent (TRIF-dependent) signaling pathways play a significant role in clearing A¿ deposits from the brain. These hypotheses are investigated in Aim 1 and 2. All TLRs, with the exception of TLR3, activate the MyD88 pathways, whereas TLR3 and TLR4 activate the TRIF pathways. We further hypothesize that TLR3 agonists are effective in ameliorating cerebral A¿-amyloidosis in an AD mouse model. The latter hypothesis is tested in Aim 2. We will test if TLR4 activation by A¿ is required for A¿ clearance by TRIF signaling in Aim 2, also. The specific aims are (Aim 1) to treat MyD88-deficient (MyD88-/-) and MyD88-sufficient (MyD88+/+) AD mouse models with TLR4 ligand or PBS (vehicle) and compare cerebral A¿ load and inflammation between the groups and (Aim 2) to treat TLR4 mutant and TLR4 wild-type AD mouse models with a TLR3 agonist or PBS and compare cerebral A¿ load and inflammation between the groups. The long term goals of this research are to determine the roles of TLR signaling in AD progression and to establish the logical basis for developing safe and effective immunotherapy for AD.

描述（由申请人提供）：阿尔茨海默病（AD）患者在大脑的神经斑块和脑血管中沉积异常聚集的淀粉样蛋白(A)。异常聚集的A¿的积累被认为是导致AD患者神经退行性变和痴呆的起始事件。因此，清除和/或防止A¿积累的治疗策略预计对AD有效。阿尔茨海默氏症大脑中的纤维蛋白A沉积伴随着激活的小胶质细胞。纤颤A可以通过toll样受体（tlr）激活小胶质细胞，包括TLR4。tlr是先天免疫系统中的一类模式识别受体。tlr的重要作用之一是激活单核细胞/小胶质细胞以应对病原体和受损的宿主细胞，并清除病原体、受损组织和积累的废物。通过TLR4激活小胶质细胞可显著促进A¿的摄入和/或清除。我们已经证明，与具有TLR4野生型等位基因的AD模型小鼠相比，TLR4功能缺失突变纯合的AD模型小鼠大脑中的a¿负荷增加。在TLR4配体的响应中，TLR4分别通过适配器蛋白、髓样分化因子88 （MyD88）和/或Toll/白细胞介素1受体结构域的适配器诱导干扰素-¿（TRIF）、MyD88依赖和MyD88独立/TRIF依赖途径发出信号。为了确定MyD88通路在A¿清除中的作用，我们研究了MyD88缺乏（MyD88-/-）对AD小鼠模型中A¿积累的影响。在AD小鼠模型中，MyD88缺乏降低了大脑A¿负荷。因此，我们假设tlr4介导的myd88依赖通路在体内加剧了脑淀粉样变性，tlr4介导的myd88独立（trf依赖）信号通路在清除大脑a沉积物中起重要作用。这些假设在Aim 1和Aim 2中进行了研究。除TLR3外，所有tlr都激活MyD88通路，而TLR3和TLR4激活TRIF通路。我们进一步假设TLR3激动剂可以有效改善AD小鼠模型中的大脑A¿-淀粉样变性。后一种假设在目标2中得到验证。我们还将测试在Aim 2中TRIF信号清除A¿是否需要TLR4被A¿激活。具体目的是（Aim 1）用TLR4配体或PBS（载药）治疗MyD88缺乏症（MyD88-/-）和MyD88足症（MyD88+/+） AD小鼠模型，比较两组间脑负荷和炎症；（Aim 2）用TLR3激动剂或PBS治疗TLR4突变型和TLR4野生型AD小鼠模型，比较两组间脑负荷和炎症。本研究的长期目标是确定TLR信号在AD进展中的作用，并为开发安全有效的AD免疫疗法奠定逻辑基础。