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

• 批准号: 10407065
• 负责人: TARA L MOORE
• 金额: $ 76.04万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10407065
• 关键词: APP-PS1; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' 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; APP-PS1; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' 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

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 正常衰老的特征是认知缺陷，尤其是在记忆（1-6）和执行的领域 功能。（1，2，7-11）证据表明这些变化不是宽度宽性皮质神经元丧失的结果， 而是归因于白质髓磷脂，轴突，突触和树突的变化和/或损失 氧化代谢和注射的变化。（12-18）进一步有越来越多的证据表明 病理tau和A-beta与年龄相关的认知下降有关，即使在没有阿尔茨海默氏症的情况下 疾病和相关痴呆症（ADRD）。那是一种潜在的疗法，间充质干细胞（MSC）具有 最近受到关注，以作为对衰老的可能干预（19-22），因为他们已知可以抑制注射 并促进组织修复和透明度。 （19，23，24）此外，我们已经证明了人类的脐带 衍生细胞和MSC衍生的细胞外蔬菜（EV），MSC的活性产物，减少注入 并增强非人类灵长类动物（NHP）的运动功能的恢复和皮质损伤后的啮齿动物（25，26） 并在体外促进轴突生长和髓鞘化。（27-37）类似地，EV已被证明可以改善认知能力 糖尿病大鼠和APP/PS1小鼠的缺陷（阿尔茨海默氏病的模型）。（24、38、39）这些EV介导 有益作用可以应用于正常衰老，私人与年龄相关的神经病理学在很大程度上尚不清楚。 但是，我们的试点数据表明，老年雌性猴子的MSC-EVS的给药会下降A-Beta 沉积。基于这些证据和我们的数据，显示了皮质后EV介导的恢复的增强 NHP受伤，我们在过去三十年中的经验（NIH-NIA计划项目 AG00001-34）表征在恒河猴中的认知功能，与生命有关 大脑的变化（40，41）评估MSC-EV在我们的恒河猴衰老模型中的影响。具体来说， 我们将研究电动汽车对减慢或反向年龄相关的认知下降的效率 炎症，髓磷脂萎缩，tau和a-beta沉积。然后，我们将量化电动汽车对还原的影响 与年龄相关的突触功能障碍和神经元电生理特性的变化。最后，我们会的 对治疗和内源性电动汽车进行深入的蛋白质组学分析，以建立活性 负责治疗效率的生物货物负荷。这项纵向，多学科研究将使光明 关于神经炎症途径的关系，髓鞘损伤和类似病理和认知 与正常衰老相关的下降，并测试电动汽车在改善这些与年龄有关的缺陷方面的效率 神经结构和功能。