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

摘要 正常衰老的特征是认知缺陷，特别是在记忆（1 - 6）和执行（1 - 6）领域。 功能（1，2，7 - 11）证据表明，这些变化不是广泛的皮质神经元丢失的结果， 而是可归因于白色物质髓鞘、轴突、突触和树突的改变和/或损失， 氧化代谢和炎症的变化。（12 - 18）此外，越来越多的证据表明， 病理性Tau和A-Beta与年龄相关的认知能力下降有关，即使没有阿尔茨海默氏症 疾病及相关痴呆（ADRD）。因此，一种潜在的治疗方法，间充质干细胞（MSC），具有 最近受到关注，作为一种可能的干预衰老，（19 - 22），因为他们是众所周知的抑制炎症 并促进组织修复和髓鞘再生。(19，23，24）此外，我们已经证明，人类脐带- MSC衍生的细胞和MSC衍生的细胞外囊泡（EV），MSC的活性产物， 并增强非人灵长类动物（NHP）和啮齿类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，电动汽车已被证明可以改善认知能力， 在糖尿病大鼠和APP/PS1小鼠（阿尔茨海默病模型）中，(24，38，39）这些EV介导的 有益的效果可以应用于灵长类动物的正常衰老和与年龄相关的神经病理学在很大程度上是未知的。 然而，我们的初步数据显示，在老年雌性恒河猴中给予MSC-EV会降低A β 证词基于这一证据和我们的数据显示，EV介导的皮质后恢复增强 在NHP的伤害，我们建立在我们的经验，在过去的三十年（NIH-NIA计划项目 AG00001 - 34）表征恒河猴在整个寿命和年龄相关的认知功能， 脑中的变化（40，41），以评估MSC-EV在我们的恒河猴衰老模型中的影响。具体地说， 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的疗效， 炎症、髓鞘萎缩以及tau和A-β沉积。然后，我们将量化电动汽车对减少 与年龄相关的突触功能障碍和神经元电生理特性的变化。最后我们将 对治疗和内源性EV进行深入的蛋白质组学分析，以建立活性成分的谱 生物负荷负责治疗效果。这种纵向的、多学科的研究将揭示 神经炎症通路、髓鞘损伤和ADRD样病理与认知功能的关系 与正常衰老相关的下降，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

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.