Mechanisms of brain rejuvenation

项目摘要/摘要 认知功能减退仍然是影响老年人健康的最大威胁之一。事实上，老龄化仍然是 痴呆相关神经退行性疾病的单一最主要危险因素，包括阿尔茨海默氏症 疾病。在考虑人口老龄化的速度时，必须确定 通过保护，甚至抵消，来保持认知完整性的手段 衰老。一种假定的教条认为，由于缺乏营养物质，衰老的大脑无法抵抗衰老的影响。 固有的可塑性，促进了与年龄相关的永久性功能障碍。我们和其他人已经开始 挑战这种教条，表明系统的操纵，如异慢性异生(在这种情况下 幼年和老年动物的循环系统是相连的)可以增强老年人的成体干细胞功能 大脑。此外，我的实验室最近证明，在老年人中，神经元和认知能力的恢复是可能的 脑部通过全身注射年轻血浆，并确定转录因子Creb是关键的 大脑恢复活力的中介物。虽然新兴的年轻化研究领域正在快速增长，但目前 到目前为止，重点一直放在识别年轻血液中的个别血液传播因素上。不过，这个 这种方法留下了一些基本的问题没有得到探索：1.年轻的年轻效果能持续多久 老年大脑上的血液？2.年轻血液在老年大脑中引发了哪些机械性变化来促进 返老还童？3.年轻血液对衰老大脑的有益影响是否延伸到与痴呆症相关的 阿尔茨海默病等神经退行性疾病？因此，拟议研究的目的是 探讨年轻血对衰老脑的滋补和治疗作用。具体地说，我们的 假设是全身暴露在年轻血液中会引起突触和认知的持久恢复。 功能，同时改善神经退行性表型。我们将用三个具体目标来测试这一理论： 1.描述全身暴露于年轻血液后脑部恢复活力的动力学。2.识别 Creb下游的分子机制是年轻血液使大脑恢复活力的基础。3.区分 年轻血液在加速衰老和阿尔茨海默病模型中的返老还童和治疗作用 疾病。最终，这些研究将通过使用返老还童来挑战大脑老化的传统观点。 年轻血液的影响，以获得对释放细胞事件所需的机制的理解 旧脑内的潜在可塑性。这一结果也将具有显著的翻译潜力，揭示了 可作为新疗法靶向改善痴呆相关神经退行性变的途径 阿尔茨海默氏症等疾病。

PROJECT SUMMARY/ABSTRACT Cognitive decline continues to be one of greatest health threats affecting the elderly. In fact, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases, including Alzheimer's disease. When considering, the rate at which the human population is aging, it becomes imperative to identify means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. We, and others, have begun to challenge such dogma by showing that systemic manipulations such as heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) can enhance adult stem cell function in the aged brain. Moreover, my lab recently demonstrated that neuronal and cognitive rejuvenation is possible in the aged brain by systemic administration of young blood plasma, and identified the transcription factor Creb as a critical mediator of brain rejuvenation. While the burgeoning field of rejuvenation research is fast growing, the current focus thus far has been placed on identifying individual blood-borne factors in young blood. However, this approach has left fundamental questions unexplored: 1. How long lasting are the rejuvenating effects of young blood on the old brain? 2. What mechanistic changes does young blood elicit in the old brain to promote rejuvenation? 3. Do the beneficial effects of young blood on the aged brain extend to dementia-related neurodegenerative diseases such as Alzheimer's disease? The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of young blood on the aged brain. Specifically, our hypothesis is that systemic exposure to young blood elicits long lasting rejuvenation of synaptic and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with three Specific Aims: 1. Characterize the kinetics of brain rejuvenation following systemic exposure to young blood. 2. Identify molecular mechanisms downstream of Creb underlying brain rejuvenation by young blood. 3. Distinguish rejuvenating versus therapeutic effects of young blood in a model of accelerated aging and Alzheimer's disease. Ultimately, these studies will challenge traditional views of brain aging by using the rejuvenating effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the latent plasticity within the old brain. The results will also have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.