The hippocampal dentate gyrus in aging and Alzheimer's disease: boosting transcription of retinoic acid-sensitive genes through vitamin A supplementation and HDAC inhibition

衰老和阿尔茨海默病中的海马齿状回：通过补充维生素 A 和抑制 HDAC 来促进视黄酸敏感基因的转录

• 批准号: 10446664
• 负责人: John Joshua Lawrence
• 金额: $ 63.68万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446664
• 关键词: Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Antioxidants; Autopsy; Behavioral; Binding; Biological Assay; Biological Availability; Clinical Trials; Complex; DNA; Data; Disease Progression; Epigenetic Process; FDA approved; Gene Expression Regulation; Gene Silencing; Genes; Genetic Transcription; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Hormones; Impairment; Knowledge; Lead; Learning; Ligand Binding; Ligands; Lipids; Longevity; Mediating; Memory; Methods; Multiomic Data; Onset of illness; Outcome Measure; Oxidative Stress; Predictive Value; Process; Proteins; Reactive Oxygen Species; Retinoic Acid Receptor; Retinoic Acid Response Element; Rodent; Role; Signal Transduction; Supplementation; Testing; Time; Transcriptional Regulation; Tretinoin; Up-Regulation; Vitamin A; age related; behavior test; cell type; dentate gyrus; dietary antioxidant; drug repurposing; gene repression; innovation; interdisciplinary approach; lipidomics; metabolomics; mouse model; multiple omics; novel strategies; oxidative damage; predictive signature; prevent; public health relevance; secondary analysis; tau Proteins; transcriptomics; translational potential

PROJECT SUMMARY / ABSTRACT The hippocampal dentate gyrus (DG), critically involved in learning and memory, is a vulnerable region in both age-related cognitive impairment (ARCD) and Alzheimer’s disease (AD). Causal upstream signaling mechanisms that lead to AD remain poorly understood. Across lifespan, excess reactive oxygen species (ROS) accumulate, causing oxidative damage to proteins, lipids, and DNA. This process is termed oxidative stress (OS). Dietary antioxidants (AOs) normally scavenge excess ROS, preventing OS. Moreover, OS triggers AO defenses, which ultimately yield to AD progression. Yet, to date, clinical trials involving AO supplementation have paradoxically failed, exposing large knowledge gaps in understanding which AO species are depleted, the time course of AO depletion, and the underlying mechanisms. The AO all-trans retinoic acid (ATRA), a bioactive form of Vitamin A (VA), serves a dual role as a ROS scavenger and hormone-like ligand for the retinoic acid receptor (RAR). Ligand binding to RARs is critical for transcriptional regulation of genes containing retinoic acid response elements (RAREs). Recent evidence from rodents has demonstrated an age-dependent homeostatic collapse in hippocampal ATRA levels. Moreover, there is increasing evidence that transcriptional silencing occurs in AD. To investigate ATRA depletion, we performed a secondary analysis of hippocampal transcriptomic data from post-mortem AD brains. ATRA-sensitive genes were downregulated, accompanied by upregulation of RAR repressors. Moreover, several histone deacetylases (HDACs) were upregulated, providing evidence for epigenetic changes. Given this strong scientific premise, we hypothesize that both ATRA bioavailability and HDAC inhibition are required to restore ATRA-mediated gene transcription and hippocampal-dependent learning. Therefore, our central hypothesis is that combining vitamin A supplementation and HDAC inhibition (HDACI) maintains hippocampal-dependent learning and RAR-sensitive gene transcription in DG more effectively than HDACi alone. Using an innovative multidisciplinary approach, we will determine effects of combining VA supplementation with HDAC inhibition on learning and transcription of RAR-sensitive genes in DG cell types. SA1 tests the hypothesis that VA supplementation alleviates AD-related learning deficits and multi- omic signatures in the DG. SA2 tests the hypothesis that HDAC inhibition alleviates AD-related learning deficits and multi-omic signatures in the DG. SA3 tests the hypothesis that combining VA supplementation and HDAC inhibition (VA+HDACI) synergistically alleviates AD-related learning deficits and multi-omic signatures in the DG beyond VA and HDACI alone. Successful completion of this project will increase knowledge of aberrant transcriptional mechanisms occurring in the DG during AD. Integrating behavioral and multi-omic data, the project will elucidate multi-omic signatures in DG that protect against AD, enable the discovery of new genes necessary for DG function, and determine the value of drug repurposing for an FDA- approved HDAC inhibitor.

项目总结/摘要 海马齿状回（DG）是学习和记忆的关键区域，是学习和记忆的脆弱区域 年龄相关性认知障碍（ARCD）和阿尔茨海默病（AD）。因果上游信号 导致AD的机制仍然知之甚少。在整个生命周期中，过量活性氧（ROS） 积累，导致蛋白质，脂质和DNA的氧化损伤。这个过程被称为氧化应激 （OS）。膳食抗氧化剂（AOs）通常抑制过量的ROS，防止OS。此外，OS触发AO 防御，最终导致AD进展。然而，到目前为止，涉及AO补充剂的临床试验 自相矛盾的失败，暴露出在理解哪些AO物种被耗尽方面存在巨大的知识缺口， AO耗竭的过程及其机制。AO全反式维甲酸（ATRA），一种生物活性形式， 维生素A（VA），作为活性氧清除剂和视黄酸受体的类似配体的双重作用 （RAR）。配体与RAR的结合对含有维甲酸反应的基因的转录调控至关重要 元素（RARE）。最近来自啮齿动物的证据表明， 海马ATRA水平此外，越来越多的证据表明，转录沉默发生在AD。 为了研究ATRA的耗竭，我们对海马转录组数据进行了二次分析， AD死后的大脑ATRA敏感基因表达下调，同时RAR表达上调 阻遏物此外，几种组蛋白脱乙酰酶（HDAC）上调，提供了证据， 表观遗传变化鉴于这一强有力的科学前提，我们假设全反式维甲酸的生物利用度和 需要HDAC抑制来恢复ATRA介导的基因转录和依赖于mRNA的转录。 学习因此，我们的中心假设是，结合维生素A补充和HDAC抑制， HDACI在DG中维持了更多的海马依赖性学习和RAR敏感基因转录， 比单独使用HDACi更有效。使用创新的多学科方法，我们将确定 联合补充VA和HDAC抑制DG中的学习和RAR敏感基因的转录 细胞类型。SA 1检验了补充VA可缓解AD相关学习障碍和多功能障碍的假设。 DG中的组学签名。SA 2检验了HDAC抑制加重AD相关学习缺陷的假设 和多组学特征SA 3测试了将VA补充和HDAC结合的假设， 抑制（VA+HDACI）协同减轻AD相关的学习缺陷和DG中的多组学特征 除了VA和HDACI之外。这个项目的成功完成将增加知识的异常 在AD期间DG中发生的转录机制。整合行为和多组学数据， 该项目将阐明DG中保护AD的多组学特征，从而发现新基因 必要的DG功能，并确定FDA批准的HDAC抑制剂的药物再利用的价值。