Signaling cascades and memory deficits during aging

描述（由申请人提供）：即使没有痴呆症，成功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来延迟、预防或治疗与不成功衰老相关的认知衰退，以改善美国老年人的健康和福祉。这项工作的总体假设是，记忆巩固缺陷是认知能力下降的早期标志。据推测，记忆缺陷是由NMDA受体（NMDAR）信号级联的激活受损引起的，该信号级联指导用于维持海马功能的基因的表达。这些研究将检查不同年龄大鼠海马体（CA1和齿状回）两个区域的信号级联，以区分何时何地首次出现与记忆缺陷相关的变化。具体目标1将结合联合收割机的行为特征，在体外电生理学，蛋白质和基因表达分析，以测试的假设，记忆巩固缺陷的能力下降，激活信号级联是重要的记忆。初步数据表明，NMDAR突触反应和ERK的活性降低，在中年和老年动物与记忆巩固缺陷相对于年龄匹配，未受损的大鼠。对脑组织的检查支持这样的观点，即缺陷与经验诱导的染色质结构变化（组蛋白乙酰化）和与突触活动相关的基因表达的减少有关。具体目标2将检验神经炎症导致信号级联下降和认知下降的假设。据预测，非甾体抗炎药（NSAID）将逆转NMDAR激活的信号级联活性的降低，并改善衰老动物的记忆力。将使用相同的技术和措施检查对照组和NSAID给药组动物。初步数据表明，记忆受损的动物表现出神经炎症的标志物，观察到与细胞应激相关的细胞因子和基因的表达增强，并且与神经炎症相关的记忆巩固缺陷可以通过NSAID治疗逆转。 公共卫生相关性：即使没有痴呆症，成功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，以延迟，预防或治疗与不成功的老龄化相关的认知下降，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