Role of BMP Signaling in the Aging Brain

项目摘要 衰老通常会导致多个认知领域的功能下降， 老年人患抑郁症和焦虑症的风险显著增加。但 这些损伤背后的生理和解剖学变化尚未完全了解。一 海马结构和连接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， 在校园相关任务上的表现。骨形态发生蛋白4（BMP 4） 在小鼠中，DG在8至52周龄之间增加超过10倍。类似的衰老- 在人DG中发现BMP 4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减少约70%。这导致 在DG中BMP信号传导的异常30倍衰老相关增加， 磷酸SMAD 1/5/8。通过脑室内输注或 noggin的转基因过表达逆转了神经发生和 认知，减少抑郁样行为。相反，转基因过表达或 老年小鼠脑室内输注BMP 4可阻止运动对 神经发生以及认知和情感行为。这些发现引出了一个假设， BMP信号的变化是神经发生和海马减少的基础， 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 诱导型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，我们将研究变化之间的潜在因果关系 在神经发生和行为方面。为了开始开发潜在的治疗方法，我们将使用 一种新的技术，球形核酸纳米颗粒缀合物（SNA），作为一种基于RNAi的 治疗方法，使我们能够特异性靶向大脑中的BMPR信号， 成人神经发生最后，我们将定义BMP的表达和细胞来源的变化 配体，受体和抑制剂在老年人海马体中，并检查相关性 BMP水平、神经发生和与年龄相关的人类认知能力下降之间的关系。目标 的研究是确定特定的分子位点， 神经系统损伤可能导致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.