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: 8534010
• 负责人: THOMAS C FOSTER
• 金额: $ 26.15万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534010
• 关键词: Age; Aging; Alzheimer' s Disease; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biology; CREB1 gene; Cellular Stress; Chromatin Structure; Cognition; Cognitive aging; Cytokine Gene; Data; Dementia; Electrophysiology (science); Epigenetic Process; Exhibits; Figs - dietary; Gene Components; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Hippocampus (Brain); Histone Acetylation; Impaired cognition; In Vitro; Inflammation; Inflammatory; Intervention; Knowledge; Link; Lipopolysaccharides; Maintenance; Measures; Mediating; Memory; Memory impairment; Molecular; N-Methyl-D-Aspartate Receptors; Personal Satisfaction; Pharmaceutical Preparations; Proteins; Publishing; Rattus; Receptor Signaling; Regulation; Relative (related person); Research; Research Design; Rodent; Signal Transduction; Slice; Stress; Synapses; Synaptic plasticity; Techniques; Technology; Testing; Time; Tissues; Training; Transcriptional Activation; Water; Western Blotting; Work; abstracting; age related; aged; brain tissue; cytokine; dentate gyrus; experience; improved; middle age; neuroinflammation; novel; prevent; protein expression; receptor function; relating to nervous system; response; synaptic function; synthetic polymer Bioplex; transmission process

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 naimals. 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 即使在没有痴呆症的情况下，成功和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以延迟、预防或治疗 与不成功衰老相关的认知衰退，以改善健康和健康- 作为年长的美国人。这项拟议工作的总体假设是，记忆 巩固缺陷是认知衰退的早期标志。据推测，记忆 缺陷是由于NMDA受体(NMDAR)信号的激活受损而导致的 指导维持海马区功能的基因表达。这些研究将检验 大鼠海马区两个区(CA1区和齿状回)的信号级联 不同的年龄，以区分何时何地与记忆缺陷相关的变化 第一次浮现。特定目标1将在体外结合行为特征 电生理学、蛋白质和基因表达分析来检验记忆的假说 整合赤字的原因是激活信号级联的能力降低 对记忆很重要。初步数据表明，NMDAR突触反应和 中老年记忆巩固动物ERK活性降低 相对于年龄匹配的未受损大鼠的缺陷。对脑组织的检查支持 认为缺陷与经验减少导致染色质变化有关的观点 结构(组蛋白乙酰化)和与突触活性相关的基因的表达。 《特定目标2》将检验神经炎症导致脑血管紧张素转换酶活力下降的假设 信号级联和认知能力下降。据预测，非类固醇抗炎 药物(非甾体抗炎药)将逆转NMDAR激活的信号级联活性的下降，并 改善衰老动物的记忆力。同样的技术和措施将用于 检查对照和非甾体抗炎药治疗的非甾体抗炎药。初步数据显示记忆力受损 动物表现出神经炎症的标志，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 神经炎症可以通过非甾体抗炎药治疗而逆转。