Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging

基因表达、补偿机制和成功的认知衰老

• 批准号: 7737824
• 负责人: Carl Wayne Cotman
• 金额: $ 35.38万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737824
• 关键词: Academic Medical Centers; Address; Age; Aging; Alleles; Animal Experimentation; Animal Model; Animals; Apolipoprotein E; Behavior; Behavioral; Biological Preservation; Brain; Brain Pathology; Brain imaging; Brain region; Brain-Derived Neurotrophic Factor; Cell physiology; Cessation of life; Clinical Pathology; Cognition; Cognitive; Cognitive aging; Collaborations; Communication; Complement; Data; Down-Regulation; Energy Metabolism; Exercise; Financial compensation; Functional disorder; Gene Expression; Genes; Genotype; Growth Factor; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Learning; Link; Maintenance; Memory; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Neurofibrillary Tangles; Pathology; Pathway interactions; Pattern; Performance; Persons; Physical activity; Population; Prefrontal Cortex; Process; Protein Biosynthesis; Proteins; Risk; Risk Factors; Rodent; Rodent Model; Senile Plaques; Structure; Structure of superior frontal gyrus; Synapses; Testing; Tissue Microarray; Transgenic Mice; Translating; Translations; Up-Regulation; Variant; Vulnerable Populations; age related; aged; aging brain; animal data; animal tissue; apolipoprotein E-3; apolipoprotein E-4; base; brain tissue; case-based; cingulate gyrus; cognitive function; cognitive reserve; cohort; design; human tissue; improved; insight; interdisciplinary approach; juvenile animal; lifestyle factors; mild neurocognitive impairment; monitoring device; mouse model; normal aging; prevent; public health relevance; relating to nervous system; response

DESCRIPTION (provided by applicant): What are the neural and behavioral profiles that serve successful cognitive aging? Because gene activity provides the fundamental building blocks for cellular function and dysfunction, gene expression patterns must be the cornerstone of successful cognitive aging. One mechanism underlying preservation or maintenance of cognitive function in aging may involve engagement of compensation, a concept that is emerging from human brain imaging data. We propose to identify possible compensatory mechanisms in aging, based on a multidisciplinary approach using microarray analyses to profile gene expression patterns in clinically well-characterized human brain tissues, complemented by animal models to test mechanisms by which physical activity prevents cognitive decline, followed by a translation of the animal data to humans. In Aim 1, a set of clinically and pathologically well-defined human tissues will be used. We hypothesize that in the presence of pathology, compensatory gene expression will be mobilized to help preserve cognitive function. To address this, cases will be divided into cognitive quintiles, from which we will select the top 20th cognitive percentile, representing successful cognitive aging. To identify possible compensatory gene mobilization, we will assess gene expression profiles in the successful aging cohort, comparing gene those with low vs moderate levels of pathology. In addition, maintaining pathology constant at a moderate level, we will assess gene expression profiles across the top 4 cognitive quintiles to identify how gene expression patterns change with declining cognition. We hypothesize that declines in cognition will be reflected in a downregulation of select gene classes and genes, particularly genes linked to synaptic integrity, plasticity and energy metabolism. Various lifestyle factors are emerging as key for successful cognitive aging, in particular, increased physical activity. Thus, in Aim 2, using both human and animal tissue, we will evaluate the hypothesis that physical activity helps maintain successful cognitive aging by engaging compensatory gene mechanisms, particularly in vulnerable populations. In aged animals showing cognitive impairment, we hypothesize that exercise will reverse the impairment and mobilize a gene profile supportive of cognition/plasticity. In transgenic mouse models carrying the ApoE4 gene, a major risk factor for cognitive decline in humans, we test the hypothesis that exercise may be paradoxically more effective in E4 than E3 animals, in improving cognitive function and mobilizing plasticity-related gene expression. Finally, we seek to translate the animal research to a set of human cases where physical activity and cognition have been monitored, using post-mortem brain tissue to analyze brain gene expression patterns in high- active vs. relatively inactive people. Taken together, our project will provide new insight into gene expression profiles in the human that underlie successful cognitive aging, which are currently unknown. PUBLIC HEALTH RELEVANCE: The human population is aging and thus there is a great need to promote successful cognitive aging. Our studies will define the gene expression profiles in the human brain of those who have achieved successful cognitive aging, and determine if exercise will build and strengthen the aging brain through action on gene expression. Accordingly, these studies will help provide a rational for including exercise as a formula to promote successful cognitive health during aging.

描述（由申请人提供）：成功认知衰老的神经和行为概况是什么？由于基因活性为细胞功能和功能障碍提供了基本的构件，因此基因表达模式必须是成功认知衰老的基石。在衰老中保存或维持认知功能的一种机制可能涉及补偿的参与，这一概念正在从人类脑成像数据中产生。我们建议基于多学科方法，使用微阵列分析来识别衰老中可能的补偿机制，以介绍临床表征良好的人脑组织中的基因表达模式，并补充了动物模型，以测试身体活动可以预防认知能力下降的机制，然后将动物数据转化为人类。在AIM 1中，将使用一组临床和病理上明确的人体组织。我们假设在存在病理学的情况下，将动员补偿性基因表达以帮助保留认知功能。为了解决这个问题，病例将分为认知五分之一，我们将从中选择前20个认知百分比，代表成功的认知衰老。为了确定可能的补偿性基因动员，我们将评估成功衰老队列中的基因表达谱，并比较患有低与中等病理水平的基因。此外，我们将在中等水平上保持病理常数，我们将评估前4个认知五分位数的基因表达谱，以确定基因表达模式如何随认知下降而变化。我们假设认知下降将反映在某些基因类和基因的下调，尤其是与突触完整性，可塑性和能量代谢相关的基因。各种生活方式因素正在成为成功认知衰老的关键，尤其是增加了体育锻炼。因此，在AIM 2中，使用人类和动物组织，我们将评估以下假设：体育活动通过吸引补偿性基因机制，尤其是在脆弱的人群中有助于维持成功的认知衰老。在表现出认知障碍的老年动物中，我们假设运动将逆转障碍并动员支持认知/可塑性的基因谱。在携带APOE4基因的转基因小鼠模型中，这是人类认知下降的主要危险因素，我们检验了以下假设：运动在E4中可能比E3动物更有效地在改善认知功能和动员可塑性相关的基因表达方面更有效。最后，我们试图将动物研究转化为一组人类病例，其中使用了验尸后的脑组织来监测体育活动和认知，以分析高活性与相对不活跃的人中的脑基因表达模式。综上所述，我们的项目将为人类的基因表达谱提供新的见解，这些基因表达概况是成功的认知衰老，这目前尚不清楚。 公共卫生相关性：人口正在衰老，因此非常需要促进成功的认知衰老。我们的研究将定义已经成功认知衰老的人的人脑中的基因表达谱，并确定运动是否会通过对基因表达的作用来建立和增强脑衰老的大脑。因此，这些研究将有助于将运动作为一种促进衰老过程中成功认知健康的公式的合理性。