Role of BMP Signaling in the Aging Brain

项目摘要 衰老通常会导致多个认知域的功能下降，而且存在 显著增加了老年人患抑郁症和焦虑症的风险。然而， 这些损伤背后的生理学和解剖学变化尚不完全清楚。一个 海马体结构和连接性的变化与衰老有关，包括 齿状回(DG)颗粒下带神经发生减少 在依赖海马体的任务中的表现。骨形态发生蛋白4水平 在8至52周龄的小鼠中，DG增加了10倍以上。类似的老化- 在人类DG中，BMP4的表达也相应增加。相反，BMP的水平 在此期间，小鼠DG中的抑制物noggin减少了约70%。这将导致一个 DG中与衰老相关的BMP信号异常增加30倍，以 Phosh-Smad1/5/8。通过脑室注射或通过以下方法减少老龄小鼠的BMP信号 转基因过表达noggin逆转神经发生和衰老相关改变 认知，它可以减少类似抑郁的行为。相反，转基因过表达或 老年小鼠脑室注射BMP4可阻止运动对小鼠的有益影响 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信号的变化是神经发生和海马区减少的基础。 与衰老相关的依赖行为。为了验证这一假设，我们将首先调查 可诱导Cre介导的BMPRII对神经干细胞的细胞和行为效应 在老龄小鼠的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 一种基于RNAi的新技术--球形核酸纳米颗粒偶联物 治疗方法使我们能够针对大脑中的BMPR信号来增强 成人神经发生。最后，我们将定义BMP在表达和细胞来源方面的变化 老年人类海马体中的配体、受体和抑制物，并检验相关性 人类BMP水平、神经发生和与年龄相关的认知衰退之间的关系。目标是 其中一项研究是确定老年人治疗干预的特定分子位点 神经系统可能会恢复正常的神经功能。

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.