Pro-youthful role of Gpld1 on regenerative and cognitive function in the aged brain

项目摘要/摘要 鉴于以下原因，确定延缓并有可能逆转与年龄相关的认知能力下降的新疗法至关重要 预计在不断增长的老年人口中，痴呆症相关疾病的发病率将会增加。锻炼有 在动物模型中已被证明能恢复衰老大脑的再生能力和认知能力。此外， 运动已被证明可以改善阿尔茨海默病患者的学习和记忆。令人兴奋的是，我们的实验室 最近证明，全身服用来自锻炼小鼠的血浆可以逆转年龄- 老年小鼠成年神经发生和认知的相关损害。我们鉴定了糖基磷脂酰肌醇 作为肝源性运动血液因子的特异性磷脂酶D1(Gpld1)-其血浆水平与 随着老年小鼠认知功能的改善，其水平在活跃的健康老年人中增加 人类。在功能上，我们表明，增加老年小鼠肝脏来源的系统性Gpld1可以改善年龄- 相关的再生性和认知障碍。这些数据提出了一些基本的问题 肝源性全身性Gpld1：全身性Gpld1对衰老大脑的恢复作用能持续多久？ 系统性Gpld1在调节运动对衰老大脑的恢复作用中起什么作用？3.什么？ 系统性Gpld1在衰老脑中的年轻化作用的分子机制？该计划的目的是 拟开展的研究旨在探讨系统性Gpld1对衰老脑的年轻化作用。具体地说，我们的 假说是，运动诱导的肝脏衍生系统Gpld1可以诱导再生的持久恢复 以及老年海马体的认知功能。我们将以三个具体目标来检验这一理论：1： 描述肝脏来源的全身性Gpld1增加后脑复苏的动力学。2：调查 运动诱导的全身性Gpld1在调节运动对老年衰老作用中的必要性 大脑。3：确定肝源性全身性Gpld1抗衰老作用的分子机制 老化的大脑。这些研究的成功完成将具有巨大的翻译潜力，揭示了 可以作为新疗法的靶向途径来改善与年龄相关的神经退行性疾病 是阿尔茨海默氏症。

PROJECT SUMMARY/ABSTRACT Identifying novel therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing elderly population. Exercise has been shown to rejuvenate regenerative capacity and cognition in the aged brain in animal models. Moreover, exercise has been shown to improve learning and memory in Alzheimer’s disease patients. Excitingly, our lab recently demonstrated that systemic administration of blood plasma derived from exercised mice reverses age- related impairments in adult neurogenesis and cognition in aged mice. We identify glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived exercise blood factor – the plasma levels of which correlate with improved cognitive function in aged mice, and the levels of which are increased in active healthy elderly humans. Functionally, we show that increasing liver-derived systemic Gpld1 in aged mice ameliorates age- related regenerative and cognitive impairments. These data raise fundamental questions as to the function of liver-derived systemic Gpld1: How long lasting are the rejuvenating effects of systemic Gpld1 on the aged brain? What is the role of systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain? 3. What molecular mechanisms underly the rejuvenating effects of systemic Gpld1 in the aged brain? The purpose of the proposed study is to investigate the rejuvenating effects of systemic Gpld1 on the aged brain. Specifically, our hypothesis is that exercise-induced liver-derived systemic Gpld1 elicits long lasting rejuvenation of regenerative and cognitive functions in the aged hippocampus. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following increased liver-derived systemic Gpld1. 2: Investigate the necessity of exercise-induced systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain. 3: Determine molecular mechanisms underlying the rejuvenating effects of liver-derived systemic Gpld1 in the aged brain. Successful completion of these studies will have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate age-related neurodegenerative diseases such as Alzheimer’s disease.