Signaling cascades and memory deficits during aging

衰老过程中的信号级联和记忆缺陷

基本信息

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
项目类别：
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&apos 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

项目摘要

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。