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) 患者会出现异常聚集的淀粉样蛋白沉积 ¿ -大脑中神经炎斑块和脑血管中的蛋白质 (A¿) 异常聚集的 A¿被认为是导致 AD 中神经变性和痴呆的始发事件，因此，需要清除和/或预防 A 的治疗策略。预计积累对 AD 有效。 AD 大脑中的沉积物伴随着激活的小胶质细胞 A¿可以通过 Toll 样受体 (TLR) 激活小胶质细胞，其中 TLR4 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/小胶质细胞以响应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着促进 A¿ 的摄入和/或清除。我们已经证明，TLR4 功能丧失突变纯合的 AD 模型小鼠的 A¿ 有所增加。与具有 TLR4 野生型等位基因的 AD 模型小鼠相比，TLR4 信号通过接头蛋白、骨髓分化因子 88 (MyD88) 和/或含有 Toll/白细胞介素 1 受体结构域的接头发出信号。 -诱导干扰素-¿ (TRIF)、MyD88 依赖性和 MyD88 独立/TRIF 依赖性途径，分别为了确定 MyD88 途径在 A¿清除后，我们研究了 MyD88 缺陷 (MyD88-/-) 对 A¿ AD 小鼠模型中 MyD88 的积累减少了脑 A¿因此，我们帮助 TLR4 介导的 MyD88 依赖性途径使大脑恶化 ¿ -体内淀粉样变性以及 TLR4 介导的 MyD88 独立（TRIF 依赖性）信号通路在清除 A¿这些假设在目标 1 和 2 中进行了研究。除 TLR3 外，所有 TLR 均激活 MyD88 通路，而 TLR3 和 TLR4 则激活 TRIF 通路。我们进一步发现 TLR3 激动剂可有效改善脑 A。 ¿ - AD 小鼠模型中的淀粉样变性。后一个假设在目标 2 中进行了测试。我们将测试 A¿ 是否激活 TLR4。是 A¿ 所必需的目标 2 中的 TRIF 信号传导也可清除，具体目标是（目标 1）用 TLR4 配体或 PBS（载体）治疗 MyD88 缺陷 (MyD88-/-) 和 MyD88 充足 (MyD88+/+) AD 小鼠模型。比较脑A?组间负荷和炎症，（目标 2）用 TLR3 激动剂或 PBS 治疗 TLR4 突变型和 TLR4 野生型 AD 小鼠模型，并比较脑 A¿这项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。