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.

摘要 阿尔茨海默病（AD）是美国一个迅速增长的健康问题，已经造成了严重的公众健康问题。 以及医疗和财务方面的个人危机。开发AD的治疗策略至关重要 重要的是，因为目前没有治愈方法。已提出β-淀粉样蛋白（Aβ）在CNS中蓄积 在AD的发病机制中起致病作用。先天免疫系统对Aβ清除的功能障碍 在脑Aβ沉积和病理进展中起关键作用。小胶质细胞和骨骼 骨髓来源的单核/巨噬细胞（BMDM）是清除CNS中Aβ的关键先天性免疫细胞。 在疾病进展过程中，小胶质细胞转变为病理表型并且不能清除Aβ。BMDM显示 在Aβ清除方面的稳健作用，揭示了开发AD Aβ清除疗法的目标。实际上 在AD患者中，用于产生BMDM的造血系统是有缺陷的。BMDM以及干细胞因子 (SCF)和粒细胞集落刺激因子（G-CSF）在AD患者中显著降低。SCF和G- CSF是调节血细胞生成的重要造血生长因子。关键是， SCF和G-CSF在产生BMDM和限制Aβ积聚中的作用可能有助于发展一种 治愈AD我们最近发现SCF+G-CSF不仅能促进BMDM的产生，而且还能促进BMDM的产生。 增加BMDM募集并增强BMDM对Aβ的吞噬作用，并最终诱导长期 对APP/PS1小鼠（一种脑淀粉样变性小鼠模型）中Aβ减少和认知改善的作用。 本项目的目的是确定SCF+G-CSF如何调节BMDM以限制Aβ蓄积， 改善APP/PS1小鼠认知功能。我们假设SCF+G-CSF增加了Aβ的清除， 淀粉样变性的大脑是通过增强BMDM的产生来协调的， 募集，以及BMDM在Aβ清除中的功能。从分子生物学到生命科学 脑成像，这一假设将通过以下3个目标进行测试：目标1将确定SCF+G- CSF增强APP/PS1小鼠BMDM的产生，目的2将研究SCF+G-CSF如何调节BMDM的进入。 Aim 3将定义SCF+G-CSF如何增加BMDM摄取， 聚集的Aβ。通过这3个目的，BMDM相关Aβ清除与 还将检查神经炎性变化。我们希望这些研究能够确定 SCF+G-CSF增加Aβ清除率和认知改善的基础。该项目具有创新性， 最初由我们小组开发的独特方法，靶向造血系统， SCF+G-CSF清除BMDM介导的Aβ。这项研究是有意义的，因为它将阐明SCF+G-CSF 改善AD样病症中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治疗已被批准， FDA用于癌症患者化疗后骨髓干细胞恢复。