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

• 批准号: 8511261
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511261
• 关键词: Acute; Adaptor Signaling Protein; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; 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

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）患者在脑神经炎斑块和脑血管中出现异常聚集的淀粉样蛋白（A）沉积。异常聚集的A ²的积累被认为是导致AD神经退行性变和痴呆的起始事件。因此，预测清除和/或预防A？积聚的治疗策略对AD有效。AD脑中的原纤维A？沉积伴随着活化的小胶质细胞。Fibrillar A？可以通过Toll样受体（TLR）（包括TLR 4）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TLR 4激活小胶质细胞显著增强A？的摄入和/或清除。我们已经证明，与具有TLR 4野生型等位基因的AD模型小鼠相比，TLR 4功能缺失突变纯合子的AD模型小鼠脑中A？负荷增加。在应答TLR 4配体时，TLR 4分别通过衔接蛋白、髓样分化因子88（MyD 88）和/或Toll/白细胞介素-1受体结构域的衔接子诱导干扰素-γ（TRIF）、MyD 88依赖性和MyD 88非依赖性/TRIF依赖性途径发出信号。为了确定MyD 88通路在A？清除中的作用，我们研究了MyD 88缺陷（MyD 88-/-）对AD小鼠模型中A？积累的影响。MyD 88缺陷降低了AD小鼠模型的脑A？负荷。因此，我们假设TLR 4介导的MyD 88依赖性通路在体内加重脑淀粉样变性，并且TLR 4介导的MyD 88非依赖性（TRIF依赖性）信号传导通路在清除脑中的A？沉积物中起重要作用。目标1和目标2对这些假设进行了研究。除了TLR 3之外，所有TLR都激活MyD 88通路，而TLR 3和TLR 4激活TRIF通路。我们进一步假设，TLR 3激动剂在改善AD小鼠模型中的脑淀粉样变性中是有效的。目标2检验了后一种假设。我们还将测试Aim 2中TRIF信号转导对A？清除是否需要A？激活TLR 4。具体目的是（目的1）治疗MyD 88缺陷型（MyD 88-/-）和MyD 88-充足用TLR 4配体或PBS（媒介物）处理（MyD 88 +/+）AD小鼠模型，并比较各组之间的脑A负荷和炎症，以及（目的2）用TLR 3激动剂或PBS处理TLR 4突变体和TLR 4野生型AD小鼠模型，并比较各组之间的脑A负荷和炎症。本研究的长期目标是确定TLR信号转导在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。