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: 9357507
• 负责人: LI-RU ZHAO
• 金额: $ 40.4万
• 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/9357507
• 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，已给公众带来了严重的困扰 以及医疗和财务层面的个人危机。制定 AD 治疗策略至关重要 重要性，因为目前尚无治愈方法。已提出 β-淀粉样蛋白 (Aβ) 在中枢神经系统中的积累 在 AD 的发病机制中发挥致病作用。 Aβ 清除的先天免疫系统功能障碍 在大脑 Aβ 沉积和病理进展中至关重要。驻留的小胶质细胞和骨骼 骨髓源性单核细胞/巨噬细胞 (BMDM) 是清除 CNS 中 Aβ 的关键先天免疫细胞。 在疾病进展过程中，小胶质细胞转变为病理表型并且无法清除 Aβ。 BMDM 显示 Aβ 消除的强大作用，揭示了开发 AD 的 Aβ 清除疗法的目标。事实上， AD 患者产生 BMDM 的造血系统有缺陷。 BMDM 以及干细胞因子 AD 患者中，SCF 和粒细胞集落刺激因子 (G-CSF) 显着减少。 SCF 和 G- CSF 是调节血细胞生成的重要造血生长因子。批判性地阐明 SCF 和 G-CSF 在生成 BMDM 和限制 Aβ 积累中的作用可能有助于开发 治愈AD。我们最近发现SCF+G-CSF不仅增强了BMDM的生成，而且还 增加 BMDM 募集并增强 BMDM 对 Aβ 的吞噬作用，最终诱导长期 APP/PS1 小鼠（脑淀粉样变性小鼠模型）中 Aβ 减少和认知改善的影响。 该项目的目标是确定 SCF+G-CSF 如何调节 BMDM 来限制 Aβ 积累和 改善 APP/PS1 小鼠的认知功能。我们假设 SCF+G-CSF 增加了 Aβ 清除率 患有淀粉样变性的大脑通过增强 BMDM 的生成来协调 募集以及 BMDM 在 Aβ 去除中的功能。使用从分子生物学到活体生物学等多种方法 脑成像，该假设将通过以下 3 个目标进行检验：目标 1 将确定 SCF+G- CSF 增强 APP/PS1 小鼠中 BMDM 的产生，目标 2 将研究 SCF+G-CSF 如何调节 BMDM 的进入 将 BMDM 导入 APP/PS1 小鼠的大脑中，目标 3 将定义 SCF+G-CSF 如何增加 BMDM 的摄取 聚集的 Aβ。通过这 3 个目标，BMDM 相关的 Aβ 去除和 还将检查神经炎症变化。我们期望这些研究能够明确其机制 SCF+G-CSF 增加 Aβ 清除率和认知改善的基础。该项目的创新之处在于 我们小组最初开发的独特方法，针对造血系统以增强 通过 SCF+G-CSF 去除 BMDM 介导的 Aβ。这项研究意义重大，因为它将揭示 SCF+G-CSF 如何 改善 AD 样疾病中有缺陷的先天免疫系统，以减少 Aβ 负荷。重要的是，这 研究可以很容易地转化为临床试验，因为 SCF+G-CSF 疗法已获得 FDA 的批准 FDA 用于癌症患者化疗后骨髓干细胞的恢复。