Protein degradation and age-related cognitive impairment

项目摘要： 发生在正常衰老以及与年龄相关的神经退行性变中的认知缺陷 疾病是一个重大的公共卫生挑战。最近的研究突出了以下问题的重要性 蛋白质在衰老过程中的动态平衡，以及在维持功能上的完整性 尤其是神经元。蛋白质降解和靶向自噬的缺陷 与包括阿尔茨海默病在内的几种神经退行性疾病有关。泛素- 蛋白酶体系统(UPS)是真核细胞中蛋白质调节的主要机制。 重要的是，我们在过去几年的研究强调了蛋白质的关键作用 突触可塑性诱导和稳定性中特定细胞活动驱动的降解 与大脑几个关键区域的记忆有关。形成以及随后的检索 简单联想记忆的使用涉及增加关键调控因子的泛素化 和结构蛋白。学习和记忆回忆也会触发CaMKII依赖 20S蛋白酶体活性增强。这份提案描述了将评估的工作 我们最近的初步观察表明，UPS功能的改变可能是一个关键因素 老年大鼠潜在的记忆障碍。在目标1下，我们将量化蛋白酶体的活性 和关键活动相关信号(例如，Rpt6的磷酸化)在青年(3个月)、中年 老龄(15mo)和老龄(22mo)动物。我们会将未受刺激的值与已见的值进行比较 在检索先前学习的信息并比较来自海马体的数据之后， 杏仁核和前额叶皮质。目标2将测试是否在饮食前使用亚甲基 蓝色，它应该上调神经元的新陈代谢和蛋白质分解能力，将拯救年龄- 记忆力和UPS活动的相关缺陷。总而言之，这套实验可以提供 与年龄相关认知的神经生物学相关的几项新工作的基础 减损。

Project abstract: The cognitive deficits that occur in normal aging as well an in age-related neurodegenerative disease are a major public health challenge. Recent work has highlighted the importance of protein homeostasis in the aging process in general, and in maintaining the functional integrity of neurons in particular. Deficits in protein degradation and targeted autophagy have been linked to several neurodegenerative disorders including Alzheimer's disease. The ubiquitin- proteasome system (UPS) is a major mechanism for protein regulation in all eukaryotic cells. Importantly, our research over the last several years has highlighted the key role of protein degradation driven by specific cellular activity in the induction and stability of synaptic plasticity related to memory in several key brain areas. The formation as well as the subsequent retrieval and use of simple associative memories involve increased polyubiquitination of key regulatory and structural proteins. Both learning and memory recall also trigger a CaMKII-dependent increase in the activity of the 20S proteasome. This proposal describes work that will evaluate our recent preliminary observation that alterations in UPS function may be a critical factor underlying memory impairments in aged rats. Under Aim 1 we will quantify proteasome activity and key activity related signals (e.g., phosphorylation of Rpt6) in young adult (3 mo), middle aged (15 mo) and aged (22 mo) animals. We will compare unstimulated values to those seen after retrieval of previously learned information and compare data from the hippocampus, amygdala, and prefrontal cortex. Aim 2 will test whether dietary pretreatment with methylene blue, which should upregulate metabolic and proteolytic capacity in neurons, will rescue age- related deficits in memory and UPS activity. Together, this set of experiments could provide the basis for several new lines of work related to the neurobiology of age-related cognitive impairment.