Extracellular Vesicle treatment and age-related neuropathology in non-human primates

非人灵长类动物的细胞外囊泡治疗和年龄相关神经病理学

基本信息

批准号：
10261505
负责人：
TARA L MOORE
金额：
$ 80.3万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261505
关键词：
APP-PS1 Affect Age Age-associated memory impairment Aging Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Atrophic Attention Autopsy Axon Biological Biological Markers Biophysics Blood Brain Brain-Derived Neurotrophic Factor Categories Cell Respiration Cells Chronic Cognition Cognitive deficits Data Dendrites Deposition Diabetes Mellitus Diffuse Electron Microscopy Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Equilibrium Female Fibrinogen Functional disorder Gene Expression Human Immunohistochemistry Impaired cognition Impairment In Vitro Inflammation Inflammatory Injury Intervention Label Light Longevity MRI Scans Macaca mulatta Mediating Memory Mesenchymal Stem Cells Microglia Modeling Molecular Monkeys Morphology Myelin Myelin Basic Proteins Nature Neurons Oligodendroglia Pathologic Pathology Pathway interactions Performance Peripheral Primates Property Proteins Proteomics Recovery Recovery of Function Rodent Rodent Model Sampling Slice Structure Synapses Synaptic Transmission Testing Training Treatment Efficacy United States National Institutes of Health Work abeta accumulation abeta deposition age related aged axon growth base beta amyloid pathology brain tissue cognitive enhancement cognitive function cognitive performance cognitive testing cytokine diabetic rat efficacy testing executive function experience extracellular vesicles hippocampal pyramidal neuron hyperphosphorylated tau improved inflammatory marker light microscopy motor function recovery mouse model multidisciplinary myelination neuroinflammation neuron loss neuropathology neurotrophic factor nonhuman primate normal aging patch clamp programs protein expression relating to nervous system remyelination synaptic function tau Proteins tissue repair white matter

项目摘要

ABSTRACT Normal aging is characterized by deficits in cognition particularly in the domains of memory (1-6) and executive function.(1, 2, 7-11) Evidence suggests these changes are not a consequence of widespread cortical neuronal loss, but rather are attributable to alteration and/or loss of white matter myelin, axons, synapses and dendrites, and changes in oxidative metabolism and inflammation.(12-18) Further there is growing evidence that accumulation of pathological Tau and A-Beta are related to age-related cognitive decline, even in the absence of Alzheimer’s Disease and Related Dementias (ADRD). Thus, one potential therapy, mesenchymal stem cells (MSCs), have recently received attention as a possible intervention in aging,(19-22) as they are known to suppress inflammation and facilitate tissue repair and remyelination. (19, 23, 24) Further, we have demonstrated that human umbilical- derived cells, and MSC-derived extracellular vesicles (EVs), the active product of MSCs, reduce inflammation and enhance recovery of motor function in non-human primates (NHP) and rodents following cortical injury(25, 26) and promote axonal growth and myelination in vitro.(27-37) Similarly, EVs have been shown to improve cognitive deficits in diabetic rats and APP/PS1 mice (model of Alzheimer’s disease).(24, 38, 39) Whether these EV-mediated beneficial effects can be applied to normal aging and age-related neuropathology in primates is largely unknown. However, our pilot data show that administration of MSC-EVs in aged female rhesus monkeys decreases A-Beta deposition. Based on this evidence and our data showing EV-mediated enhancement of recovery after cortical injury in NHPs, we build upon on our experience over the past three decades (NIH-NIA Program Project AG00001-34) characterizing cognitive function in the rhesus monkey across the life-span and age-related changes in the brain (40, 41) to assess the impact of MSC-EVs in our rhesus monkey model of aging. Specifically, we will investigate the efficacy of EVs to slow or reverse age-related cognitive decline and reduce markers of inflammation, myelin atrophy, and tau and A-Beta deposition. We will then quantify the effects of EVs on reducing age-related synaptic dysfunction and changes in electrophysiological properties of neurons. Finally, we will conduct an in-depth proteomic analysis of treatment and endogenous EVs to establish the profile of the active biological cargo load responsible for treatment efficacy. This longitudinal, multi-disciplinary study will shed light on the relationships of neuroinflammatory pathways, myelin damage and ADRD like pathology and cognitive decline associated with normal aging, and test the efficacy of EVs in ameliorating these age-related deficits in neural structure and function.

抽象的正常衰老的特点是认知缺陷，特别是在记忆 (1-6) 和执行领域 (1, 2, 7-11) 有证据表明这些变化并不是广泛的皮质神经元损失的结果，而是归因于白质髓磷脂、轴突、突触和树突的改变和/或损失，并且氧化代谢和炎症的变化。(12-18) 此外，越来越多的证据表明，即使没有阿尔茨海默病，病理性 Tau 蛋白和 A-Beta 蛋白也与年龄相关的认知能力下降有关因此，间充质干细胞（MSC）是一种潜在的治疗方法。最近作为一种可能的衰老干预措施而受到关注，(19-22)，因为众所周知它们可以抑制炎症 (19,23,24)此外，我们已经证明人类脐带- 衍生细胞和 MSC 衍生的细胞外囊泡 (EV)（MSC 的活性产物）可减轻炎症并增强非人类灵长类动物 (NHP) 和啮齿动物皮质损伤后运动功能的恢复 (25, 26) 并在体外促进轴突生长和髓鞘形成。(27-37) 同样，EV 已被证明可以改善认知能力糖尿病大鼠和 APP/PS1 小鼠（阿尔茨海默病模型）中的缺陷。(24,38,39)这些 EV 介导的有益效果可应用于正常衰老，而灵长类动物与年龄相关的神经病理学在很大程度上尚不清楚。然而，我们的试验数据表明，对老年雌性恒河猴施用 MSC-EV 会降低 A-Beta 基于这一证据和我们的数据显示 EV 介导的皮质恢复增强。 NHP 中的伤害，我们以过去三十年的经验为基础（NIH-NIA 项目 AG00001-34）描述恒河猴整个生命周期和年龄相关的认知功能大脑的变化 (40, 41) 以评估 MSC-EV 对我们的恒河猴衰老模型的影响。我们将研究电动汽车减缓或逆转与年龄相关的认知能力下降并减少认知衰退标志物的功效然后我们将量化 EV 对减少炎症、髓磷脂萎缩以及 tau 和 A-Beta 沉积的影响。最后，我们将讨论与年龄相关的突触功能障碍和神经元电生理特性的变化。对治疗和内源性 EV 进行深入的蛋白质组学分析，以确定活性物质的概况这项纵向、多学科研究将揭示生物负载对治疗效果的影响。神经炎症通路、髓磷脂损伤和ADRD（如病理学和认知）之间的关系与正常衰老相关的衰退，并测试 EV 在改善这些与年龄相关的缺陷方面的功效神经结构和功能。