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.

摘要 阿尔茨海默病(AD)在美国是一个迅速增长的健康问题，已经给公众造成了严重的 以及医疗和财务层面的个人危机。开发治疗阿尔茨海默病的策略至关重要 这很重要，因为目前还没有治愈方法。β-淀粉样蛋白(A-β)在中枢神经系统的蓄积已被提出 在阿尔茨海默病的发病中起致病作用。先天免疫系统功能障碍对β清除的影响 在大脑Aβ沉积和病理进展中起关键作用。留存的小胶质细胞和骨 骨髓来源的单核/巨噬细胞(BMDM)是清除中枢神经系统中Aβ的关键先天免疫细胞。 在疾病发展过程中，小胶质细胞转变为病理表型，无法清除Aβ。BMDM展示 Aβ消除的强效，揭示了开发AD的Aβ清除疗法的目标。事实上， AD患者生成BMDM的造血系统存在缺陷。BMDM与干细胞因子 AD患者外周血中SCF和G-CSF水平明显降低。SCF和G- 脑脊液是调节血细胞生成的重要造血生长因子。批判性地，澄清 干细胞因子和粒细胞集落刺激因子在BMDM生成和限制β蓄积中的作用可能有助于 治疗阿尔茨海默病。我们最近发现，SCF+G-CSF不仅能促进BMDM的生成，而且还能 增加骨髓基质募集和增强骨髓基质对Aβ的吞噬作用，最终诱导长期 对脑淀粉样变性模型APP/PS1小鼠Aβ降低和认知改善的影响。 本项目的目的是明确干细胞因子+粒细胞集落刺激因子是如何调节BMDM以限制Aβ蓄积和 改善APP/PS1小鼠的认知功能。我们推测，干细胞因子+粒细胞集落刺激因子-增加A-β清除。 淀粉样变性的大脑通过促进BMDM的生成、BMDM的生成来协调 BMDM在Aβ清除中的作用。使用从分子生物学到生命的各种方法 脑成像，这一假说将通过以下3个目标进行验证：目标1将确定SCF+G- CSF促进APP/PS1小鼠BMDM产生，Aim 2将研究SCF+G-CSF如何调节BMDM进入 BMDM进入APP/PS1小鼠的大脑，目标3将定义SCF+G-CSF如何增加BMDM对 聚合Aβ。通过这三个目标，与BMDM相关的Aβ去除和 还将检查神经炎性变化。我们希望这些研究能够确定这些机制 干细胞因子+粒细胞集落刺激因子-增加Aβ清除和认知改善。该项目在以下方面具有创新性 最初由我们团队开发的以造血系统为靶点的独特方法，以增强 骨髓基质介导的干细胞+粒细胞集落刺激因子清除A-β这项研究具有重要意义，因为它将揭示SCF+G-CSF如何 改善类AD状态下先天免疫系统缺陷，降低A-β负荷。重要的是，这 这项研究可以很容易地转化为临床试验，因为SCF+G-CSF疗法已经获得了 美国食品和药物管理局对癌症患者化疗后骨髓干细胞的恢复。