Role of BMP Signaling in the Aging Brain

BMP 信号传导在大脑衰老中的作用

• 批准号: 9378036
• 负责人: JOHN A KESSLER
• 金额: $ 31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378036
• 关键词: Ablation; Affect; Affective; Age; Age-Months; Age-associated memory impairment; Aging; Aging-Related Process; Anatomy; Anxiety; Anxiety Disorders; Autopsy; Behavior; Behavioral; Biochemical; Brain; Cognition; Cognitive; Development; Exercise; Genetic; Goals; Growth; Hippocampus (Brain); Human; Impairment; Intervention; Intraventricular Infusion; Knowledge; Label; Lead; Ligands; Measures; Mediating; Mental Depression; Molecular; Mus; Nervous System Physiology; Nervous system structure; Organ; Performance; Peripheral; Physiological; Proliferation Marker; Property; RNA Interference Therapy; Receptor Signaling; Risk; Rodent; Role; Signal Transduction; Spherical Nucleic Acids; Stem cells; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; adult neurogenesis; age related; aged; aging brain; aging hippocampus; bone morphogenetic protein 4; bone morphogenetic protein receptor type II; bone morphogenetic protein receptors; cell type; cognitive function; cognitive performance; cognitive task; dentate gyrus; functional decline; improved; inhibitor/antagonist; nanoparticle; nerve stem cell; neuroblast; neurogenesis; new technology; nonhuman primate; overexpression; prevent; receptor; receptor expression; relating to nervous system; stem; targeted treatment; therapeutic target

Project Summary Aging often leads to a functional decline across multiple cognitive domains, and there is a signficantly increased risk of depression and anxiety disorders in the aged. However, the physiologic and anatomic changes underlying these impairments are not fully understood. A number of changes in hippocampal structure and connectivity are associated with aging including a decline in neurogenesis in the subgranular zone of the dentate gyrus (DG) and decreased performance on hippocampus-dependent tasks. Levels of bone morphogenetic protein 4 (BMP4) in the mouse DG increase more than 10-fold between 8 and 52 weeks of age. A similar aging- related increase in BMP4 expression is found in the human DG. Conversely, levels of the BMP inhibitor, noggin, in the mouse DG decrease by about 70% during this time. This results in an extraordinary 30-fold aging-related increase in BMP signaling in the DG measured by levels of phosph-SMAD1/5/8. Reducing BMP signaling in aged mice by either intraventricular infusion or transgenic overexpression of noggin reverses aging-related changes in both neurogenesis and cognition, and it reduces depression-like behavior. Conversely, transgenic overexpression or intraventricular infusion of BMP4 in aged mice prevents the beneficial effects of exercise on neurogenesis and on cognitive and affective behavior. These findings lead to the hypothesis that changes in BMP signaling underlie the decreases in neurogenesis and in hippocampus- dependent behavior associated with aging. To test this hypothesis, we will first investigate the cellular and behavioral effects of inducible cre-mediated ablation of BMPRII in neural stem cells in the DG of aged mice. We then will examine the potential causal relationship between changes in neurogenesis and behavior. To begin to develop a potential therapeutic approach, we will use a new technology, spherical nucleic acid nanoparticle conjugates (SNAs), as an RNAi-based therapeutic approach to enable us to specifically target BMPR signaling in the brain to enhance adult neurogenesis. Finally, we will define changes in expression and cellular origin of BMP ligands, receptors, and inhibitors in the hippocampus of aging humans and examine correlations between BMP levels, neurogenesis, and age-associated cognitive decline in humans. The goal of the studies is to identify specific molecular loci where therapeutic intervention in the aged nervous system may lead to a return to normal neurological function.

项目概要 衰老通常会导致多个认知领域的功能下降，并且有一个 老年人患抑郁症和焦虑症的风险显着增加。然而， 这些损伤背后的生理和解剖学变化尚不完全清楚。一个 海马结构和连接性的许多变化与衰老有关，包括 齿状回 (DG) 颗粒下区神经发生下降 海马体依赖性任务的表现。骨形态发生蛋白 4 (BMP4) 水平 小鼠 DG 在 8 至 52 周龄期间增加了 10 倍以上。类似的老化—— 在人类 DG 中发现了 BMP4 表达的相关增加。相反，BMP 的水平 在此期间，小鼠 DG 中的抑制剂 noggin 减少了约 70%。这导致 通过以下水平测量，DG 中的 BMP 信号传导与衰老相关的异常增加了 30 倍 磷酸化-SMAD1/5/8。通过脑室内输注或减少老年小鼠的 BMP 信号传导 noggin 的转基因过度表达可逆转神经发生和衰老相关的变化 认知，并减少类似抑郁的行为。相反，转基因过度表达或 老年小鼠心室内注射 BMP4 可防止运动对健康的有益影响 神经发生以及认知和情感行为。这些发现导致了这样的假设： BMP 信号传导的变化是神经发生和海马体减少的基础 与衰老相关的依赖行为。为了检验这个假设，我们首先要调查 诱导性 cre 介导的 BMPRII 消融对神经干细胞的细胞和行为影响 在老年小鼠的 DG 中。然后我们将检查变化之间的潜在因果关系 在神经发生和行为方面。为了开始开发一种潜在的治疗方法，我们将使用 一种新技术，球形核酸纳米粒子缀合物（SNA），作为一种基于 RNAi 的 治疗方法使我们能够专门针对大脑中的 BMPR 信号传导，以增强 成人神经发生。最后，我们将定义 BMP 表达和细胞起源的变化 老年人海马体中的配体、受体和抑制剂并检查相关性 BMP 水平、神经发生和人类与年龄相关的认知能力下降之间的关系。目标 这些研究的目的是确定对老年人进行治疗干预的特定分子位点 神经系统可能会导致恢复正常的神经功能。