Signaling cascades and memory deficits during aging

衰老过程中的信号级联和记忆缺陷

• 批准号: 9266698
• 负责人: THOMAS C FOSTER
• 金额: $ 29.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266698
• 关键词: Age; Aging; Alzheimer' s Disease; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Award; Behavior; Behavioral; Blood specimen; Brain; Brain region; Cellular Stress; Chromatin Structure; Cognitive; Cognitive aging; Cytokine Gene; Data; Dementia; Diagnostic; Early Diagnosis; Elderly; Electrophysiology (science); Exhibits; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Transfer; Genes; Genetic Transcription; Goals; Health; Hippocampus (Brain); Histone Acetylation; Impaired cognition; Impairment; In Vitro; Inflammation; Intervention; Learning; Link; Location; Measures; Medial; Mediating; Memory; Memory Loss; Memory impairment; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neocortex; Neuroimmune; Oxidative Stress; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prefrontal Cortex; Publishing; Rattus; Research; Reverse Transcription; Serum; Serum Markers; Short-Term Memory; Signal Transduction; Specificity; Stress; Synapses; System; Technical Expertise; Techniques; Testing; Training; Viral; Viral Vector; Water; Work; age related; aged; brain tissue; cognitive process; cytokine; dentate gyrus; experience; improved; inflammatory marker; information processing; killings; massive parallel processing; memory consolidation; middle age; neuroinflammation; novel; overexpression; predictive marker; prevent; protein expression; relating to nervous system; response; spatial memory; synaptic function

Summary/Abstract Even in the absence of dementia, a dichotomy remains between successful and unsuccessful cognitive aging. The long range goal is to provide interventions to delay, prevent, or treat cognitive decline associated with unsuccessful aging in order to improve the health and well- being of older Americans. The overall hypothesis for the proposed work is that memory consolidation deficits are an early marker of cognitive decline. It is hypothesized that memory deficits result from impaired activation of NMDA receptor (NMDAR) signaling cascades that direct the expression of genes for maintaining hippocampal function. The studies will examine signaling cascades in two fields of the hippocampus (CA1 and the dentate gyrus) of rats at different ages in order to distinguish when and where changes associated with memory deficits first emerge. Specific aim 1 will combine behavioral characterization, in vitro electrophysiology, protein and gene expression analyses to tests the hypothesis that memory consolidation deficits result from a decreased ability to activate signaling cascades that are important for memory. Preliminary data indicates that NMDAR synaptic responses and the activity of ERK is decreased in middle-aged and aged animals with memory consolidation deficits relative to aged-matched, unimpaired rats. Examination of brain tissue supports the idea that deficits are associated with a reduction in experience induced changes in chromatin structure (histone acetylation) and the expression of genes related to synaptic activity. Specific aim 2 will test the hypothesis that neural inflammation contributes to the decline in the signaling cascade and cognitive decline. It is predicted that non-steroidal anti-inflammatory drugs (NSAIDs) will reverse the decrease in NMDAR activated signaling cascade activity and improve memory in aging animals. The same techniques and measures will be used to examine control and NSAID treated animals. Preliminary data indicates that memory impaired animals exhibit markers of neuroinflammation observed as enhanced expression of cytokines and genes related to cellular stress and memory consolidation deficits associated with neuroinflammation can be reversed by NSAID treatment.

摘要/摘要 即使没有痴呆症，成功与不成功之间仍然存在二分法 认知老化。长期目标是提供干预措施来延迟、预防或治疗 与衰老相关的认知能力下降，以改善健康状况 是年长的美国人。所提出的工作的总体假设是记忆 巩固缺陷是认知能力下降的早期标志。假设记忆 NMDA 受体 (NMDAR) 信号级联激活受损导致的缺陷 指导维持海马功能的基因表达。研究将考察 大鼠海马两个区域（CA1 和齿状回）的信号级联 不同年龄，以区分与记忆缺陷相关的变化的时间和地点 首先出现。具体目标 1 将结合体外行为特征 电生理学、蛋白质和基因表达分析来检验记忆的假设 整合缺陷是由于激活信号级联的能力下降而导致的 对记忆很重要。初步数据表明 NMDAR 突触反应和 记忆巩固的中老年动物ERK活性降低 与年龄匹配、未受损的大鼠相比存在缺陷。脑组织检查支持 认为缺陷与经验引起的染色质变化减少有关 结构（组蛋白乙酰化）和与突触活动相关的基因表达。 具体目标 2 将检验神经炎症导致神经功能下降的假设 信号级联和认知能力下降。据预测，非甾体类抗炎药 药物（NSAID）将逆转 NMDAR 激活的信号级联活性的下降， 提高衰老动物的记忆力。将使用相同的技术和措施 检查对照和 NSAID 治疗的动物。初步数据表明记忆受损 动物表现出神经炎症标志物，表现为细胞因子表达增强 以及与细胞应激和记忆巩固缺陷相关的基因 NSAID 治疗可以逆转神经炎症。