AGING AND THE NEURONAL CYTOSKELETON

越来越多的证据表明神经细胞钙调节失调 动态平衡导致与年龄相关的认知缺陷和 神经元对退化的脆弱性增加。最近， 大鼠脑海马神经元显示出戏剧性的年龄- L型压敏钙活性的相关升高 提示钙离子通过这种途径进入体内可能 改变神经元中正常的突触信号机制。这位飞行员 该项目旨在考察L式渠道对 突触后细胞骨架蛋白MAP2的调控。上一首 研究表明，MAP2的磷酸化状态为 受钙依赖的信号通路调节，包括 钙依赖蛋白磷酸酶。因此，这个项目将 检验老化的海马体更容易患脑血管疾病的假设 靶向蛋白磷酸酶的钙依赖激活 Map2.磷酸化状态的改变是主要的 调节蛋白质结构和功能的方式， 与之相比，老年人大脑的这种结构变化可能会有所不同 敬年轻的成年人。多条证据表明，蛋白质 磷酸酶是上下文中研究的合乎逻辑的主题 正常衰老的。此外，MAP2是一种突触后细胞骨架 受神经活动调节的蛋白质，假设为 帮助控制可塑性和稳定性之间的平衡 神经元树突。因此，这些研究总体上是相关的。 了解细胞骨架调节的可能机制 在衰老的退行性疾病中走错了路。此外，他们还将 有助于我们理解蛋白质的调节机制 结构在正常老化过程中。

Accumulating evidence implicates dysregulation of neuronal calcium homeostasis contributing both to age-related cognitive deficits and to increased vulnerability of neurons to degeneration. Recently, rat brain hippocampal neurons were shown to exhibit a dramatic age- related increase in the activity of L-type voltage-sensitive calcium channels, suggesting that calcium entry through such channels may alter normal synaptic signaling mechanisms in neurons. This pilot project seeks to examine the contribution of L-type channels to regulation of the postsynaptic cytoskeletal protein MAP2. Previous studies have shown that the phosphorylation state of MAP2 is regulated by calcium-dependent signaling pathways, including calcium-dependent protein phosphatases. This project therefore will test the hypothesis that aged hippocampus is more susceptible to calcium-dependent activation of protein phosphatases that target MAP2. Alterations in phosphorylation state are one of the primary ways in which the structure and function of proteins are regulated, and such structural changes may differ in the aged brain as compared to the young adult. Several lines of evidence suggest that protein phosphatases are logical subjects of investigation in the context of normal aging. Furthermore, MAP2 is a postsynaptic cytoskeletal protein that is regulated by neural activity and is hypothesized to help control the balance between plasticity and stability of neuronal dendrites. These studies, therefore, are generally relevant to understanding mechanisms of cytoskeletal regulation that may go awry in degenerative diseases of aging. In addition, they will contribute to our understanding of mechanisms regulating protein structure during normal aging.