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（由适用提供）：阿尔茨海默氏病（AD）患者在神经斑块和大脑中的神经斑块和脑血管中发展了绝对骨料淀粉样蛋白（a。）的沉积物。绝对汇总A的积累被发布为发射事件，导致AD中的神经变性和痴呆症。因此，预计明确和/或预防A积累的理论策略将有效地抗AD。 AD大脑中的原纤维a的沉积物伴随着活化的小胶质细胞。 Fibrillara¿可以通过包括TLR4在内的Toll样受体（TLR）激活小胶质细胞。 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对病原体和受损宿主细胞的响应，清除病原体，组织受损的组织和积累废物的单核细胞/小胶质细胞。小胶质细胞通过TLR4的激活显着增强了A的摄入和/或清除率。我们已经表明，与带有TLR4野生型等位基因的AD模型小鼠相比，TLR4功能丧失突变的纯合小鼠的A负载增加。为了响应TLR4配体，TLR4通过衔接蛋白发出信号，髓样分化因子88（MyD88）和/或Toll/Toll/Interleukin-1受体域受ADAPTOR诱导的Interferon-¿（TRIF），MyD88依赖性和依赖性的pathertional诱导。为了确定MyD88途径在清除率中的作用，我们研究了MyD88缺陷（MyD88 - / - ）对AD鼠标模型中A的影响的影响。 MyD88缺乏在AD鼠标模型中降低了脑A的负载。因此，我们假设TLR4介导的MyD88依赖性途径加剧了体内大脑�-淀粉样变性，并且TLR4介导的MyD88独立（TRIF依赖性）信号通路在清除大脑中清除A沉积物中起着重要作用。这些假设在AIM 1和2中进行了研究。除TLR3外，所有TLR都激活了MyD88途径，而TLR3和TLR4激活了TRIF途径。我们进一步假设TLR3激动剂可有效改善AD小鼠模型中的淀粉样变性。后一个假设在AIM 2中进行了测试。我们将测试是否还需要A a tlr4激活A a a a trif信号在AIM 2中。 The specific aims are (Aim 1) to treat MyD88-deficiency (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比较两组之间的脑载荷和炎症。这项研究的长期目标是确定TLR信号在AD进程中的作用，并为开发AD的安全有效免疫疗法的逻辑基础。