Protein degradation and age-related cognitive impairment

蛋白质降解和年龄相关的认知障碍

• 批准号: 9329354
• 负责人: FRED J HELMSTETTER
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329354
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Aging-Related Process; Alzheimer' s Disease; Amygdaloid structure; Animals; Area; Attenuated; Autophagocytosis; Behavioral; Behavioral Assay; Biological; Brain; Brain region; Cell Aging; Cells; Chronic; Cognitive deficits; Data; Development; Diet; Disease model; Dorsal; Eukaryotic Cell; Foundations; Functional disorder; Future; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Laboratories; Laboratory Rat; Learning; Link; Longevity; Memory; Memory impairment; Metabolic; Methylene blue; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Organism; Performance; Phosphorylation; Polyubiquitin; Polyubiquitination; Prefrontal Cortex; Process; Proteins; Proteolysis; Public Health; Rattus; Receptor Activation; Regulation; Regulatory Pathway; Research; Retrieval; Risk Factors; Sampling; Signal Transduction; Structural Protein; Synaptic plasticity; System; Testing; Therapeutic Intervention; Ubiquitin; Update; Work; age related; aged; aging brain; behavioral outcome; calmodulin-dependent protein kinase II; cellular longevity; cognitive function; cognitive performance; conditioned fear; experience; experimental study; genetic regulatory protein; improved; interest; juvenile animal; long term memory; memory process; memory recall; memory retrieval; middle age; multicatalytic endopeptidase complex; normal aging; protein degradation; proteostasis; relating to nervous system; response; targeted treatment; young adult

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.

项目摘要： 认知缺陷发生在正常衰老以及与年龄相关的神经退行性疾病中， 疾病是一个重大的公共卫生挑战。最近的工作突出了以下方面的重要性： 蛋白质稳态在衰老过程中的一般，并在维持功能完整性 尤其是神经元。蛋白质降解和靶向自噬的缺陷已经被发现。 与包括阿尔茨海默氏症在内的几种神经退行性疾病有关。泛蛋白- 蛋白酶体系统（UPS）是真核细胞中蛋白质调控的主要机制。 重要的是，我们过去几年的研究突出了蛋白质的关键作用， 在突触可塑性的诱导和稳定中由特定细胞活动驱动的降解 与记忆有关的几个关键脑区。形成以及随后的回收 简单联想记忆的使用涉及增加关键调节蛋白的多聚泛素化， 和结构蛋白质。学习和记忆回忆也会触发依赖于CaMKII的 增加20 S蛋白酶体的活性。本提案描述了将评估 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，我们将定量蛋白酶体活性 以及关键活动相关信号（例如，Rpt 6磷酸化）在年轻成人（3个月），中期 老龄（15个月）和老龄（22个月）动物。我们将比较未受刺激的值和 在检索先前学习的信息并比较来自海马体的数据之后， 杏仁核和前额叶皮层目标2将测试是否饮食预处理亚甲基 蓝色，它应该上调神经元的代谢和蛋白水解能力，将拯救年龄- 记忆力和UPS活动的相关缺陷。总之，这组实验可以提供 与年龄相关的认知神经生物学相关的几条新工作线的基础 损伤