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：
8039627
负责人：
THOMAS C FOSTER
金额：
$ 29.21万
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/8039627
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 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 receptor function relating to nervous system response synaptic function synthetic polymer Bioplex transmission process

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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

描述（由申请人提供）：即使在缺乏痴呆症的情况下，成功和失败的认知衰老之间仍然存在二分法。远距离目标是提供干预措施，以延迟，预防或治疗与不成功衰老有关的认知下降，以改善老年人的健康和福祉。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。假设记忆缺陷是由NMDA受体（NMDAR）信号级联激活受损而导致的，该信号指导基因表达以维持海马功能。这些研究将检查不同年龄段的大鼠海马（CA1和齿状回）的两个田间的信号级联，以区分与记忆缺陷有关的何时何地变化。特定的目标1将结合行为表征，体外电生理学，蛋白质和基因表达分析，以检验以下假设：记忆巩固缺陷是由于激活对记忆很重要的信号级联的能力降低而导致的。初步数据表明，与年龄匹配的，未损坏的大鼠相对于中年和老年动物，NMDAR突触反应和ERK活性降低。脑组织的检查支持了这样一种观念，即缺乏与经验降低染色质结构（组蛋白乙酰化）和与突触活动相关的基因的表达相关的观念。具体目标2将检验以下假设：神经炎症有助于信号级联和认知能力下降的下降。可以预测，非甾体类抗炎药（NSAIDS）将逆转NMDAR激活的信号级联活性的减少并改善衰老动物的记忆力。相同的技术和措施将用于检查对照和NSAID治疗的动物。初步数据表明，记忆障碍动物表现出的神经炎症的标志物被认为是增强的细胞因子表达和与细胞应激和记忆巩固与神经炎症相关的基因的表达，可以通过NSAID治疗反转。公共卫生相关性：即使在缺乏痴呆症的情况下，成功和失败的认知衰老之间仍然存在二分法。远距离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下降，以改善美国人的健康和福祉