Altering immune tolerance in Alzheimer disease

改变阿尔茨海默病的免疫耐受性

• 批准号: 9979733
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979733
• 关键词: Abeta clearance; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; B-Lymphocytes; Behavioral; Brain; C Type Lectin Receptors; CD14 gene; Candida albicans; Cell Wall; Cell physiology; Cells; Cerebrum; Chemicals; Chronic; Clinical; Cognitive deficits; Complex; Deposition; Development; Disease Progression; Endotoxins; Epigenetic Process; Etiology; Euglena gracilis; Exposure to; Gene Expression; Gene Mutation; Genetic Recombination; Genetic Risk; Genetic study; Goals; Growth Factor; Hippocampus (Brain); Immune; Immune Tolerance; Immunity; Immunologic Memory; Immunology; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Injections; Innate Immune Response; Innate Immune System; Late Onset Alzheimer Disease; Ligands; Ligation; Lipid A; Lipopolysaccharides; Measures; Metabolic; Microglia; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuronal Plasticity; Neurons; PTPRC gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern recognition receptor; Phagocytes; Phagocytosis; Phenotype; Physiological; Play; Prevention; Preventive; Preventive measure; Production; Resistance; Role; Senile Plaques; Signal Transduction; T-Lymphocyte; TLR2 gene; TLR4 gene; TLR6 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Training; Transcriptional Activation; adaptive immunity; beta-Glucans; brain parenchyma; chemokine; cytokine; cytotoxic; dectin 1; hyperphosphorylated tau; improved; in vivo; macrophage; microorganism; monocyte; mouse model; neuroinflammation; neuronal survival; pathogen; protein aggregation; receptor; response; risk variant; tau Proteins; transcription factor; transgenic model of alzheimer disease; wasting

Altering immune tolerance in Alzheimer disease Amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein in the brain are two main pathological changes in patients with Alzheimer’s disease (AD). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. The causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular pathways that can modulate the progression of the vast majority of AD cases for development of preventive and therapeutic measures. Many lines of evidence support the notion that activated microglia, innate immune cells in the central nervous system, play pivotal, dual roles in AD progression: either clearing Aβ deposits by phagocytosis and promoting neuron survival and plasticity or releasing cytotoxic chemicals and inflammatory cytokines, exacerbating Aβ load and causing neurodegeneration. Activating microglia with a beneficial phenotype should have clinically vital importance in AD therapy and prevention. C-type lectin receptors including dectin-1 and toll-like receptors (TLRs) including TLR4 are classes of pattern-recognition receptors in the innate immune system. One of the important roles of these receptors is to activate microglia in response to pathogens and damaged host cells and to clear pathogens, damaged tissues, and accumulated wastes. Activation of microglia through certain TLRs can markedly boost ingestion and clearance of Aβ. Indeed, treatments of AD mouse models with certain TLR agonists activate microglia, decrease cerebral Aβ deposits and NFTs, and improve cognitive deficits. However, prolonged exposure to certain TLR agonists, such as lipopolysaccharide (LPS), induce hyporesponsiveness to subsequent TLR agonist challenges (endotoxin/TLR tolerance), leading to immune paralysis. Because Aβ aggregates are a TLR agonist, we hypothesize that chronic exposure of microglia to Aβ aggregates induces Aβ/TLR tolerance, leading to decreased clearance of Aβ aggregates and reduced neuronal survival and plasticity in AD and its animal models. We found that an AD mouse model becomes hypo-responsive to a TLR4 agonist, LPS, after cerebral Aβ deposition (tolerance). Activation of dectin-1 signaling reverses or counteracts LPS tolerance in monocytes. We hypothesize that dectin-1 signaling enhances clearance of Aβ deposits and ameliorates cognitive deficits in an AD mouse model by counteracting and reversing “LPS/Aβ tolerance”. This hypothesis will be tested by carrying out the following aims. In Aim 1, we will produce a dectin-1-deficient (clec7a-/-) AD mouse model and determine its effects on AD-pathology and behavioral functions. In Aim 2, we will inject a dectin-1 ligand into the hippocampi of dectin-1-deficient and -sufficient AD mouse models and determine its effects on AD pathology and behavioral functions. The long term goals of this study are to determine the role of dectin-1 signaling in the AD pathogenesis and to develop new preventive and therapeutic strategies for AD.

改变阿尔茨海默病的免疫耐受 淀粉样斑块由异常聚集的淀粉样β蛋白（Aβ）和神经胶质细胞沉积组成， 由脑中过度磷酸化的tau蛋白的异常聚集体组成的缠结（NFT）是两种主要的 阿尔茨海默病（AD）患者的病理变化。淀粉样斑块和NFT伴随 慢性炎症的特征是小胶质细胞活化和细胞因子增加。造成这种情况的原因 大多数AD病例尚不清楚，且尚无满意的AD治疗和预防措施。 因此，迫切需要鉴定可以调节肿瘤进展的分子途径。 绝大多数AD病例的预防和治疗措施的发展。多方面证据 支持这样的观点，即激活的小胶质细胞，中枢神经系统中的先天免疫细胞， 在AD进展中的作用：通过吞噬作用清除Aβ沉积，促进神经元存活和可塑性 或释放细胞毒性化学物质和炎性细胞因子，加剧Aβ负荷， 神经变性激活具有有益表型的小胶质细胞在AD中具有重要的临床意义 治疗和预防。C型凝集素受体，包括dectin-1和Toll样受体（TLR），包括TLR 4 是先天免疫系统中的模式识别受体。其中一个重要的作用是 受体的作用是激活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， 受损的组织和累积的废物。通过某些TLR激活小胶质细胞可以显著增强 Aβ的摄取和清除。事实上，用某些TLR激动剂治疗AD小鼠模型激活了 小胶质细胞，减少脑Aβ沉积和NFT，并改善认知缺陷。然而，长期 暴露于某些TLR激动剂，例如脂多糖（LPS），诱导对随后的TLR激动剂的低反应性。 TLR激动剂激发（内毒素/TLR耐受性），导致免疫麻痹。因为Aβ聚集体是一种 TLR激动剂，我们假设小胶质细胞长期暴露于Aβ聚集体诱导Aβ/TLR耐受， 导致AD患者Aβ聚集体清除率降低，神经元存活率和可塑性降低， 动物模型我们发现，AD小鼠模型对TLR 4激动剂LPS的反应性降低， 大脑Aβ沉积（耐受性）。dectin-1信号的激活逆转或抵消LPS耐受， 单核细胞我们假设dectin-1信号通路增强了Aβ沉积物的清除，并改善了认知功能。 通过抵消和逆转“LPS/Aβ耐受性”来改善AD小鼠模型中的缺陷。这一假设将得到检验 实现以下目标。在目标1中，我们将产生dectin-1缺陷型（clec 7a-/-）AD小鼠模型， 确定其对AD病理学和行为功能的影响。在目标2中，我们将dectin-1配体注射到 Dectin-1缺陷和不足AD小鼠模型的细胞凋亡，并确定其对AD病理学的影响 和行为功能。本研究的长期目标是确定dectin-1信号转导在细胞凋亡中的作用。 探讨AD的发病机制，并提出新的防治策略。