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

抗氧化剂的作用

• 批准号: 7511617
• 负责人: Elizabeth Head
• 金额: $ 1.2万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511617
• 关键词: Age; Aging; Aging-Related Process; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Animals; Antioxidants; Apoptosis; Archives; Area; Base of the Brain; Behavioral; Bioinformatics; Biological Models; Brain; Canis familiaris; Carnitine; Categories; Clinic; Clinical Trials; Cognition; Cognitive; Combined Modality Therapy; Computer software; Data; Data Analyses; Deposition; Detection; Diet; Dietary Intervention; Dietary Supplementation; Dose; Down-Regulation; Employee Strikes; Exercise; Experimental Designs; Freezing; Funding; Future; Gene Expression; Genes; Genome; Growth Factor; Hippocampus (Brain); Human; Human Genome; Impaired cognition; Individual; Inflammation; Intervention; Intervention Studies; Laboratories; Lead; Learning; Link; Lipids; Maintenance; Maps; Measures; Memory; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Nature; Nerve Degeneration; Neurobiology; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Numbers; Outcome Measure; Overlapping Genes; Pathology; Pathway interactions; Pattern; Process; Protein Precursors; Proteins; Proteomics; Public Health; RNA; Reagent; Research; Reverse Transcriptase Polymerase Chain Reaction; Score; Senile Plaques; Signal Transduction; Synaptic plasticity; Technology; Testing; Thinking; Thioctic Acid; Time; Tissue Sample; Tissues; Training; Translating; Treatment outcome; Up-Regulation; Vitamin E; abeta accumulation; age related; aged; aging brain; base; beta amyloid pathology; brain tissue; cognitive function; combinatorial; experience; feeding; fruits and vegetables; functional improvement; functional outcomes; improved; innovation; juvenile animal; neurobiological mechanism; neurogenesis; neuron loss; neuropathology; normal aging; novel therapeutics; research study; response; social; treatment effect

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.

描述（由申请人提供）：在衰老过程中，存在许多可能导致神经元功能障碍和认知受损的大脑变化。高等动物模型对于理解脑老化的分子和细胞基础至关重要。我们一直在使用老年犬（狗）模型，以确定关键的干预措施和脑老化的分子机制。与人类相似，老年犬脑中记忆和学习能力沿着下降，并伴有氧化损伤、神经元丢失和2-淀粉样蛋白（A2）沉积的进行性累积。犬A2与人A2相同，内源性蓄积水平与人相似，A2斑块负荷与认知功能相关。因此，该模型系统可用于探索衰老，氧化损伤，A2和认知之间的联系。我们已经使用了饮食和环境丰富的干预，以确定这些是否可以改善认知功能单独和组合。我们已经证明，抗氧化剂和线粒体辅助因子的饮食干预可以改善老年犬的学习能力，并在2.8年的时间内保持认知功能。沿着学习能力的提高，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降低氧化损伤。我们进一步表明，行为丰富也可以改善认知，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，抗氧化剂饮食或行为富集治疗单独的有益认知效果在组合时进一步增强。目前，每种治疗的分子靶点和两种治疗之间的汇合点，导致额外的神经元功能的改善尚未建立。本申请的主要目的是利用最新可用技术（Affyscore犬基因组阵列），并利用这些相同动物的脑组织，进一步建立和绘制每种治疗和联合治疗的认知改善作用的神经生物学机制。为了实现这些目标，提出了以下目标：（1）在狗的颞顶皮层中的基因表达变化作为年龄的函数;（2）在提供了富含抗氧化剂的饮食和行为富集的老年狗中的基因表达变化。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，治疗方法和结果测量，这些可能直接转化为人类临床试验。公共卫生关系：分析老年犬抗氧化饮食和行为富集干预的结果基因表达变化将使我们能够识别和优化用于改善正常衰老个体和阿尔茨海默病患者认知的新疗法。