Signaling cascades and memory deficits during aging

描述(由申请人提供)：即使在没有痴呆症的情况下，成功的认知老化和不成功的认知老化之间仍然存在二分法。长期目标是提供干预措施，以延缓、预防或治疗与不成功老龄化相关的认知衰退，以改善美国老年人的健康和福祉。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NMDAR(NMDAR)信号通路的激活受损导致的，NMDAR信号通路指导维持海马区功能的基因的表达。这项研究将检测不同年龄大鼠海马区(CA1和齿状回)两个区域的信号级联，以区分与记忆缺陷相关的变化最早出现的时间和地点。特定目标1将结合行为特征、体外电生理学、蛋白质和基因表达分析来测试记忆巩固缺陷是由于激活对记忆至关重要的信号级联的能力降低所致的假说。初步数据表明，记忆巩固缺陷的中老年动物的NMDAR突触反应和ERK活性低于老年匹配的未受损大鼠。对脑组织的检查支持这样一种观点，即缺陷与经验的减少有关，染色质结构的改变(组蛋白乙酰化)和与突触活动相关的基因表达。具体目标2将测试神经炎症导致信号级联下降和认知下降的假设。据预测，非类固醇抗炎药(NSAIDs)将逆转NMDAR激活的信号级联活性的下降，改善衰老动物的记忆。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动物。初步数据表明，记忆受损的动物表现出神经炎症的标志，观察到细胞因子和与细胞应激相关的基因表达增强，以及与神经炎症相关的记忆巩固缺陷可以通过非类固醇激素治疗而逆转。 与公共健康相关：即使在没有痴呆症的情况下，成功的认知老化和不成功的认知老化之间仍然存在二分法。长期目标是提供干预措施，以延缓、预防或治疗与不成功老龄化相关的认知衰退，以改善美国老年人的健康和福祉。

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