Effect of Antioxidants & Behavioral Enrichment on Gene Expression in Aged Canines

描述（由申请人提供）：在衰老过程中，大脑会发生一些变化，可能导致神经元功能障碍和认知受损。高等动物模型对于理解脑衰老的分子和细胞基础至关重要。我们一直在使用老年犬模型来确定脑衰老的关键干预措施和分子机制。随着年龄的增长，记忆力和学习能力的衰退以及氧化损伤的逐渐积累、神经元的丧失和2-淀粉样蛋白（A2）的沉积在衰老的狗大脑中发生，与人类相似。犬类A2与人类A2相同，内源性积累水平与人类相似，A2斑块负荷与认知功能相关。因此，该模型系统对于探索衰老、氧化损伤、A2和认知之间的联系是有用的。我们使用饮食和环境富集干预来确定它们是否能单独或联合改善认知功能。我们已经证明，在2.8年的时间里，抗氧化剂和线粒体辅助因子饮食干预可以改善老年狗的学习和维持认知功能。随着学习能力的提高，我们观察到抗氧化剂治疗犬的A2降低，并使用蛋白质组学方法减少氧化损伤。我们进一步表明，行为富集也可以改善认知，但这是通过非A2/斑块机制发生的，因为A2似乎不受影响。重要的是，单独抗氧化饮食或行为强化治疗的有益认知效果在联合使用时进一步增强。目前，每种治疗的分子靶点和两种治疗之间导致神经元功能改善的交汇点尚未确定。本应用程序的主要目的是利用最新可用的技术（Affymetrix犬基因组阵列），并利用这些动物的脑组织进一步建立和绘制每种治疗和联合治疗的认知改善效果背后的神经生物学机制。为了实现这些目标，提出了以下目标：(1)分析狗的颞顶叶皮层基因表达变化作为年龄的函数；(2)分析老年犬在提供或同时提供富含抗氧化剂的饮食和行为富集后基因表达的变化。进一步了解这两种干预措施所涉及的途径可能会导致新的研究假设、治疗和结果测量，这些假设、治疗和结果测量可能会直接转化为人类临床试验。公共卫生相关性：分析老年犬抗氧化饮食和行为富集干预导致的基因表达变化将使我们能够识别和优化新的治疗方法，以改善正常衰老个体和阿尔茨海默病患者的认知能力。

DESCRIPTION (provided by applicant): During aging, there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage, neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2, accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus, this model system is useful for exploring links between aging, oxidative damage, A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly, beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present, the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and; (2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses, treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease.