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性 淀粉样斑块由异常聚集的淀粉样 β 蛋白 (Aβ) 和神经原纤维沉积物组成 由大脑中过度磷酸化 tau 蛋白异常聚集组成的缠结 (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 以小胶质细胞激活和细胞因子增加为特征的慢性炎症。造成广大的原因 大多数AD病例是未知的，并且没有令人满意的AD治疗和预防措施。 因此，迫切需要确定可以调节疾病进展的分子途径。 绝大多数AD病例需要制定预防和治疗措施。许多证据 支持以下观点：激活的小胶质细胞（中枢神经系统中的先天免疫细胞）发挥着关键的、双重的作用 AD 进展中的作用：通过吞噬作用清除 Aβ 沉积物并促进神经元存活和可塑性 或释放细胞毒性化学物质和炎症细胞因子，加剧 Aβ 负荷并导致 神经变性。激活具有有益表型的小胶质细胞在 AD 治疗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 TLR4） 是先天免疫系统中的一类模式识别受体。这些的重要作用之一 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， 组织受损，废物堆积。通过某些 TLR 激活小胶质细胞可以显着增强 Aβ的摄入和清除。事实上，用某些 TLR 激动剂治疗 AD 小鼠模型会激活 小胶质细胞，减少大脑 Aβ 沉积和 NFT，并改善认知缺陷。然而，长期 接触某些 TLR 激动剂，例如脂多糖 (LPS)，会导致后续反应的反应性低下 TLR 激动剂挑战（内毒素/TLR 耐受），导致免疫瘫痪。因为 Aβ 聚集体是 TLR 激动剂，我们假设小胶质细胞长期暴露于 Aβ 聚集体会诱导 Aβ/TLR 耐受， 导致 AD 及其相关疾病中 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 小鼠模型在 TLR4 激动剂 LPS 后变得反应低下。 脑 Aβ 沉积（耐受性）。 dectin-1 信号传导的激活可逆转或抵消 LPS 耐受性 单核细胞。我们假设 dectin-1 信号传导增强 Aβ 沉积物的清除并改善认知能力 通过抵消和逆转“LPS/Aβ 耐受性”来抑制 AD 小鼠模型中的缺陷。这个假设将被检验 通过实现以下目标。在目标 1 中，我们将制作 dectin-1 缺陷型 (clec7a-/-) 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 配体注入 dectin-1 缺陷和充足 AD 小鼠模型的海马并确定其对 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 信号传导在 AD 发病机制并制定新的 AD 预防和治疗策略。