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: 10180811
• 负责人: JOHN A KESSLER
• 金额: $ 30.7万
• 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/10180811
• 关键词: Ablation; Affect; Affective; Age; Age-Months; Age-associated memory impairment; Aging; Anatomy; Anxiety; Anxiety Disorders; Autopsy; BMPR2 gene; 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; Process; Proliferation Marker; Property; RNA Interference Therapy; Receptor Signaling; Risk; Rodent; Role; Signal Transduction; Spherical Nucleic Acids; 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 receptors; cell type; cognitive function; cognitive performance; cognitive task; dentate gyrus; druggable target; 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; stem cells; 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.

项目摘要 衰老通常会导致多个认知领域的功能下降，并且有一个 年龄较大的抑郁症和焦虑症的风险显着增加。但是， 这些障碍的基础生理和解剖变化尚不完全了解。一个 海马结构和连通性的变化数与衰老有关 齿状回（DG）的下粒区域神经发生下降，并下降 海马依赖性任务的性能。骨形态发生蛋白4的水平（BMP4） 在小鼠中，在8至52周龄之间增加了10倍以上。类似的老化 - 在人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降低了约70％。这导致 DG中BMP信号传导的非凡30倍与老化有关的增加 磷-Smad1/5/8。通过脑室内输注或 Noggin的转基因过表达逆转了与衰老有关的神经发生和衰老相关的变化 认知，它减少了抑郁症的行为。相反，转基因过表达或 在老年小鼠中脑室室内输注BMP4可防止运动对 神经发生以及认知和情感行为。这些发现导致了以下假设 BMP信号传导的变化是神经发生和海马 - 与衰老相关的依赖行为。为了检验这一假设，我们将首先研究 BMPRII在神经干细胞中BMPRII的诱导型CRE介导的消融的细胞和行为影响 在老鼠的DG中。然后，我们将研究变化之间的潜在因果关系 在神经发生和行为中。为了开始开发潜在的治疗方法，我们将使用 一种新技术，即球形核酸纳米颗粒偶联物（SNA），作为基于RNAi的 治疗方法使我们能够专门针对大脑中的BMPR信号以增强 成人神经发生。最后，我们将定义BMP的表达和细胞起源的变化 衰老人类海马中的配体，受体和抑制剂并检查相关性 在BMP水平，神经发生和人类与年龄相关的认知下降之间。目标 研究的是确定特定的分子基因座，在老年人中进行治疗干预 神经系统可能导致恢复正常的神经功能。

项目成果

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

为什么有些小鼠比其他小鼠更聪明：骨形态发生蛋白信号对认知的影响。

• DOI: 10.1523/eneuro.0213-22.2022
• 发表时间: 2023
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Bonds,JacquelineA;Tunc-Ozcan,Elif;Dunlop,SaraR;Rawat,Radhika;Peng,Chian-Yu;Kessler,JohnA
• 通讯作者: Kessler,JohnA