Mechanisms of brain rejuvenation

大脑年轻化的机制

• 批准号: 9483605
• 负责人: SAUL A VILLEDA
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9483605
• 关键词: Address; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Automobile Driving; Behavioral Paradigm; Bioluminescence; Blood; Brain; Cardiovascular system; Cell physiology; ChIP-seq; Cognitive; Dementia; Elderly; Environment; Event; Exhibits; Exposure to; Functional disorder; Gene Targeting; Genetic Transcription; Health; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Kinetics; Knowledge; Learning; Left; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parabiosis; Pathway interactions; Plasma; Population; Predisposition; RNA Interference; Radial; Rejuvenation; Research; Risk Factors; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Viral; Virus; Water; adult stem cell; age effect; age related; age related neurodegeneration; aged; aging brain; aging hippocampus; arm; base; cognitive enhancement; cognitive function; combat; conditioned fear; functional disability; in vivo; insight; mouse model; neurodegenerative phenotype; new therapeutic target; novel strategies; overexpression; synaptic function; synaptogenesis; theories; transcription factor

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.

项目概要/摘要 认知能力下降仍然是影响老年人的最大健康威胁之一。事实上，衰老仍然是 痴呆相关神经退行性疾病（包括阿尔茨海默病）的单一最主要危险因素 疾病。在考虑人口老龄化速度时，必须确定 通过防止甚至抵消以下因素的影响来维持认知完整性的方法： 老化。预设的教条认为，由于缺乏老化的大脑，因此无法对抗衰老的影响。 固有的可塑性促进与年龄相关的永久性功能障碍。我们和其他人已经开始 通过展示诸如异时性联体共生（其中 年轻和年老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 脑。此外，我的实验室最近证明，老年人的神经元和认知复兴是可能的 通过全身注射年轻血浆来大脑，并确定转录因子 Creb 是一个关键的 大脑再生的中介者。虽然复兴研究这一新兴领域正在快速发展，但目前 迄今为止，重点是确定年轻血液中的个体血源性因子。然而，这 这种方法留下了一些尚未探讨的基本问题： 1. 年轻化的恢复效果能持续多久？ 老脑子里有血？ 2. 年轻的血液在年老的大脑中引起什么机制变化以促进 回春？ 3. 年轻血液对老年大脑的有益影响是否会延伸到与痴呆症相关的领域？ 阿尔茨海默病等神经退行性疾病？因此，拟议研究的目的是 研究年轻血液对衰老大脑的恢复和治疗作用。具体来说，我们的 假设是，全身接触年轻血液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。我们将通过三个具体目标来检验这一理论： 1. 表征全身暴露于年轻血液后大脑恢复活力的动力学。 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 加速衰老和阿尔茨海默病模型中年轻血液的恢复与治疗效果 疾病。最终，这些研究将通过使用恢复活力的方法来挑战大脑衰老的传统观点。 年轻血液的影响，以获得释放所需的细胞事件的机制理解 旧大脑中潜在的可塑性。研究结果还将具有重大的转化潜力，揭示 可以作为改善痴呆相关神经退行性新疗法的目标途径 阿尔茨海默病等疾病。