Innate immunity in Alzheimer's disease: Role of toll-like receptor signaling

阿尔茨海默氏病的先天免疫：Toll 样受体信号传导的作用

• 批准号: 7904117
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 31.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904117
• 关键词: Acute-Phase Proteins; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid Proteins; Amyloidosis; Animal Model; Animals; Behavioral; Brain; Cells; Cerebrum; Complement; Conflict (Psychology); Dementia; Dependovirus; Deposition; Disease; Disease Progression; Elderly; Etiology; Event; Functional disorder; Gene Delivery; Genetic; Goals; Immune; Immune response; Immune system; In Vitro; Inflammation; Ingestion; Interleukin-10; Interleukin-17; Interleukin-6; Ligands; Lipopolysaccharides; Mediating; Microglia; Modality; Molecular Profiling; Mouse Cell Line; Mouse Strains; Mus; Mutation; Myelogenous; Names; Natural Immunity; Nerve Degeneration; Neuraxis; Partner in relationship; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Peptide Hydrolases; Phagocytes; Play; Proteins; Receptor Signaling; Recombinant adeno-associated virus (rAAV); Research; Role; Senile Plaques; Signal Transduction; Signaling Molecule; Staging; TLR4 gene; Testing; Tissue Sample; Tissues; Toll-like receptor 6; Toll-like receptors; Transgenic Mice; Up-Regulation; cerebrovascular; chemokine; cognitive function; congenic; cytokine; cytotoxic; gene therapy; improved; in vivo; lipoteichoic acid; mouse model; mutant; novel; overexpression; pathogen; prevent; public health relevance; receptor; response; wasting

DESCRIPTION (provided by applicant): Patients with Alzheimer's disease (AD) develop deposits of aggregated amyloid ¿-protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. Fibrillar A2 deposits in AD brain are accompanied by innate immune responses such as activated microglia and increased levels of cytokines. Accumulating evidence supports the hypothesis that activated microglia, innate immune cells in the central nervous system, play a pivotal role in the AD progression: either clearing A¿ deposits by phagocytic activity or releasing cytotoxic substances. Toll-like receptors (TLRs) are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate phagocytes/microglia to respond to insults including pathogens and damaged host cells, leading to clearance of pathogens, damaged tissues and accumulated wastes. We hypothesize that these protective functions are mediated by MyD88-dependent pathways and that A¿ load in the brain can be modulated by TLR4 signaling. We will determine the roles of MyD88-dependent pathways and TLR4 signaling in A¿ clearance by completing the Specific Aim 1 and 2. We further hypothesize that A¿ load in the brain and cognitive functions are modulated by TLR4 effector cytokines/chemokines, which will be tested by performing Aim 3. In Aim 4, we will test the hypothesis that accumulation of A¿ in the brain induces dysfunction of TLR4 signaling in microglia resulting in exacerbation of A¿ deposition in AD patients and AD mouse models. Specific Aims are (Aim 1) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models on a MyD88-deficient genetic background, (Aim 2) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models that overexpress TLR4, (Aim 3a) to compare cerebral cytokine and chemokine expression profiles between TLR4 wild-type and mutant AD mouse models, (Aim 3b) to overexpress TLR4 effector cytokines and/or chemokines in the brain via adeno-associated virus gene delivery and determine cerebral A¿ load, inflammation and behavioral deficits in the AD mouse models, and (Aim 4) to determine whether A¿ induces dysfunction of TLR signaling, using cultured microglia, AD mouse models and tissue samples from AD patients. The long term goal of this research is to determine the roles of TLR signaling and its effector cytokines/chemokines in the AD progression. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. Patients with AD develop deposits of aggregated amyloid 2 protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. This study will elucidate the mechanisms by which A¿ deposits are cleared and serve as a proof of principle to demonstrate if our novel cytokine/chemokine gene therapy modality is effective in treating an animal model of AD.

描述（由适用提供）：患有阿尔茨海默氏病（AD）的患者在大脑中形成淀粉样蛋白（a。）的总沉积物。积累被认为是AD病因中的因果事件。 AD大脑中的Fibrilar A2沉积物伴随着先天免疫反应，例如活化的小胶质细胞和细胞因子水平升高。积累的证据支持了以下假设：中枢神经系统中活化的小胶质细胞，先天免疫细胞，在AD进展中起关键作用：通过吞噬活性清除A的沉积物或释放细胞毒性物质。 Toll样受体（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吞噬细胞/小胶质细胞，以应对包括病原体和受损宿主细胞在内的侮辱，从而导致病原体，损坏的组织和累积废物的清除。我们假设这些受保护的功能是由MyD88依赖性途径介导的，并且大脑中的负载可以通过TLR4信号传导调节。我们将通过完成特定的目标1和2来确定依赖MyD88依赖性途径和TLR4信号传导的作用。我们进一步假设大脑中的A负载和认知功能受到TLR4效应细胞因子/趋化因子/趋化因子的调节，通过在AIM 4中测试AIM 4。小胶质细胞中的TLR4信号传导导致AD患者和AD小鼠模型的A沉积加剧。 Specific Aims are (Aim 1) to determine cerebral A¿ load, inflammation and behavioral defines in AD mouse models on a MyD88-deficiency genetic background, (Aim 2) to determine cerebral A¿ load, inflammation and behavioral defines in AD mouse models that overexpress TLR4, (Aim 3a) to compare cerebral cytokine and chemokine expression profiles between TLR4 wild-type and mutant AD mouse模型（目标3B）通过腺体相关病毒基因的递送来过表达大脑中的TLR4效应细胞因子和/或趋化因子，并确定AD小鼠模型中的负载，炎症和行为定义的负载，炎症和行为定义，（AIM 4）使用AD培养的小鼠模型和AD培养的Mictog cromber and cyplate shime condece condece condection and cardection Migalog模型，并确定AD型的模型。这项研究的长期目标是确定TLR信号传导及其效应子细胞因子/趋化因子在AD进程中的作用。公共卫生相关性：阿尔茨海默氏病（AD）是古老的痴呆症最常见的原因。但是，迄今为止，AD尚无满意工厂治疗。 AD患者在大脑中形成淀粉样蛋白2蛋白（a）的沉积物。积累被认为是AD病因中的因果事件。这项研究将阐明清除A沉积物的机制，并作为原理证明，以证明我们的新型细胞因子/趋化因子基因治疗方式是否有效地治疗AD的动物模型。