Alterations in BMP Signaling in the Aging Brain

 描述(申请人提供)：衰老通常会导致多个认知领域的功能衰退，但这些损伤背后的生理和解剖变化尚不完全清楚。海马区结构和连接性的一些变化与衰老有关，包括齿状回(DG)颗粒下区神经发生的下降，以及在海马区依赖任务中表现的下降。小鼠DG中的骨形态发生蛋白4(BMP4)水平在8到52周之间增加了10倍以上。在人类DG中也发现了类似的与年龄相关的BMP4表达增加。相反，在此期间，小鼠DG中BMP抑制物noggin的水平下降了约70%。这导致DG中与衰老相关的BMP信号异常增加30倍，以Phosph-Smad1/5/8水平衡量。通过脑室注射或转基因过表达noggin来减少老龄小鼠的BMP信号可以逆转与衰老相关的神经发生和认知变化。相反，转基因过表达或在老年小鼠脑室内注射BMP4会阻止运动对神经发生和认知能力的有益影响。这些发现导致了一种假设，即BMP信号的变化是与衰老相关的神经发生和海马体依赖行为减少的基础。为了验证这一假设，我们将首先研究可诱导cre介导的BMPRII在老年小鼠DG神经干细胞(NSCs)中的细胞和行为效应。为了确定与衰老相关的神经干细胞静止相关的BMP靶点，我们将对从BMPRII完整和消融的老年小鼠分离的神经干细胞进行基因组水平的基因表达谱分析。最后，我们将确定BMP配体、受体和抑制物在老年人类海马区的表达和细胞来源的变化，并检查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相关性。这项研究的目标是确定在老年神经系统中进行治疗干预可能会导致正常神经功能恢复的特定分子位点。

 DESCRIPTION (provided by applicant): Aging often leads to a functional decline across multiple cognitive domains, but 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. Conversely, transgenic overexpression or intraventricular infusion of BMP4 in aged mice prevents the beneficial effects of exercise on neurogenesis and cognitive performance. 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 the DG neural stem cells (NSCs) of aged mice. To identify BMP targets associated with aging related neural stem cell quiescence, we will perform genomic scale gene expression profiling of NSCs isolated from BMPRII intact and ablated aged mice. 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 human. 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.