Targeting the hematopoietic system: the role of hematopoietic growth factors in restricting A-beta accumulation in Alzheimers disease

靶向造血系统：造血生长因子在限制阿尔茨海默病中 A-β 积累中的作用

• 批准号: 9377021
• 负责人: LI-RU ZHAO
• 金额: $ 7.52万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9377021
• 关键词: APP-PS1; Abeta clearance; Address; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Blood Cells; Bone Marrow; Bone Marrow Stem Cell; Brain; Brain imaging; CCR5 gene; Cancer Patient; Cell Differentiation process; Cell Survival; Cells; Cerebrum; Clinical; Clinical Trials; Cognitive; Data; Dementia; Deposition; Development; Disease; Disease Progression; Endothelial Cells; Excision; FDA approved; Functional disorder; Generations; Granulocyte Colony-Stimulating Factor; Health; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic System; Hematopoietic stem cells; Immune; Immune system; Impaired cognition; Impairment; In Vitro; Innate Immune System; Life Cycle Stages; Light; Long-Term Effects; Longevity; Mediating; Medical; Microglia; Molecular Biology; Molecular and Cellular Biology; Mus; Pathogenesis; Pathologic; Patients; Phagocytosis; Phenotype; Plasma; Play; Production; Publishing; Recovery; Recruitment Activity; Regulation; Research; Role; Stem Cell Factor; System; TLR2 gene; Testing; Therapeutic; Translating; United States; abeta accumulation; base; cerebral amyloidosis; chemotherapy; cognitive function; enhancing factor; fighting; improved; in vivo; innovation; macrophage; monocyte; mouse model; neuroinflammation; novel therapeutic intervention; novel therapeutics; public health relevance; recombinase-mediated cassette exchange; repaired; uptake

Abstract Alzheimer's disease (AD), a rapidly growing health problem in the United States, has created serious public and personal crises at both medical and financial levels. Developing therapeutic strategies for AD is of critical importance, as no cure is currently available. Accumulation of β-amyloid (Aβ) in the CNS has been proposed to play a causative role in the pathogenesis of AD. Dysfunction of the innate immune system for Aβ clearance is crucially involved in cerebral Aβ deposition and in pathological progression. The resident microglia and bone marrow-derived monocytes/macrophages (BMDMs) are the key innate immune cells to clear Aβ in the CNS. During disease progression, microglia turn to a pathological phenotype and fail to clear Aβ. BMDMs show robust effects in Aβ elimination, revealing a target for developing Aβ clearance therapies for AD. In fact, the hematopoietic system for generating BMDMs is defective in AD patients. BMDMs as well as stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) are significantly reduced in AD patients. SCF and G- CSF are the essential hematopoietic growth factors that regulate blood cell generation. Critically, elucidating the role of SCF and G-CSF in generating BMDMs and in restricting Aβ accumulation may help in developing a cure for AD. We have recently discovered that SCF+G-CSF not only enhances BMDM generation but it also increases BMDM recruitment and enhances BMDM phagocytosis of Aβ, and ultimately induces long-term effects in Aβ reduction and cognitive improvement in APP/PS1 mice, a mouse model of cerebral amyloidosis. The objective of this project is to define how SCF+G-CSF regulates BMDMs to restrict Aβ accumulation and improve cognitive function in APP/PS1 mice. We hypothesize that the SCF+G-CSF-increased Aβ clearance in the brain with amyloidosis is coordinated through the enhancement of BMDM generation, of BMDM recruitment, and of BMDM function in Aβ removal. Using approaches ranging from molecular biology to live brain imaging, this hypothesis will be tested through the following 3 Aims: Aim 1 will determine how SCF+G- CSF enhances BMDM production in APP/PS1 mice, Aim 2 will examine how SCF+G-CSF regulates entry of BMDMs into the brains of APP/PS1 mice, and Aim 3 will define how SCF+G-CSF increases BMDM uptake of aggregated Aβ. Through these 3 Aims, the interaction between BMDM-related Aβ removal and neuroinflammatory changes will also be examined. We expect these studies to define the mechanisms underlying the SCF+G-CSF-increased Aβ clearance and cognitive improvement. This project is innovative in the unique approach, originally developed by our group, of targeting the hematopoietic system to enhance BMDM-mediated Aβ removal by SCF+G-CSF. This study is significant as it will shed light on how SCF+G-CSF ameliorates the defective innate immune system in the AD-like condition to reduce Aβ load. Importantly, this research could be readily translated into clinical trials because SCF+G-CSF therapy has been approved by the FDA for bone marrow stem cell recovery after chemotherapy in cancer patients.

抽象的 阿尔茨海默氏病（AD）是美国一个迅速增长的健康问题，已经建立了严重的公众 以及医疗和财务水平的个人犯罪。制定广告的治疗策略至关重要 重要性，因为目前尚无治疗。已经提出了CNS中β-淀粉样蛋白（Aβ）的积累 在AD的发病机理中发挥致命作用。 Aβ清除率的先天免疫系统功能障碍 完全参与脑Aβ沉积和病理进展。居民小胶质细胞和骨头 骨髓来源的单核细胞/巨噬细胞（BMDMS）是清除CNS中Aβ的关键先天免疫细胞。 在疾病进展过程中，小胶质细胞转向病理表型，无法清除Aβ。 BMDMS显示 在Aβ演化中的鲁棒作用，揭示了为AD开发Aβ清除疗法的靶标。实际上， 用于产生BMDM的造血系统在AD患者中有缺陷。 BMDM和干细胞因子 AD患者（SCF）和粒细胞 - 固体刺激因子（G-CSF）显着降低。 SCF和G- CSF是调节血细胞产生的基本造血生长因子。批判性，阐明 SCF和G-CSF在产生BMDM和限制Aβ积累中的作用可能有助于开发A 治愈广告。我们最近发现SCF+G-CSF不仅增强了BMDM的生成 增加BMDM募集并增强Aβ的BMDM吞噬作用，并最终诱导长期 APP/PS1小鼠的Aβ还原和认知改善的影响，APP/PS1小鼠是脑淀粉样变性的小鼠模型。 该项目的目的是定义SCF+G-CSF如何调节BMDM以限制Aβ的积累和 改善APP/PS1小鼠的认知功能。我们假设在 通过增强BMDM的BMDM，具有淀粉样变性的大脑是协调的 募集和BMDM在Aβ去除中的功能。使用从分子生物学到生活的方法 大脑成像，该假设将通过以下3个目标进行检验：AIM 1将决定SCF+g-如何 CSF增强了APP/PS1小鼠的BMDM生产，AIM 2将检查SCF+G-CSF如何调节进入 BMDM进入APP/PS1小鼠的大脑，AIM 3将定义SCF+G-CSF如何增加BMDM的摄取 聚集的Aβ。通过这三个目标，与BMDM相关的Aβ的去除与 还将检查神经炎症性变化。我们希望这些研究能定义机制 SCF+G-CSF增强的Aβ清除率和认知改善的基础。这个项目是创新的 最初是由我们小组开发的独特方法，旨在针对造血系统来增强 通过SCF+G-CSF去除BMDM介导的Aβ。这项研究很重要，因为它将阐明SCF+G-CSF 在类似AD的条件下改善了先天免疫系统以减少Aβ负载。重要的是，这个 研究很容易被转化为临床试验，因为SCF+G-CSF疗法已得到已批准 癌症患者化学疗法后骨髓干细胞恢复的FDA。