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.

项目摘要 /摘要 在学习和记忆中涉及的海马齿状回（DG）是两者中的一个脆弱区域 与年龄相关的认知障碍（ARCD）和阿尔茨海默氏病（AD）。因果上游信号传导 导致广告的机制仍然很少理解。在整个寿命中，多活性氧（ROS）过多 积累，对蛋白质，脂质和DNA造成氧化损伤。该过程称为氧化应激 （OS）。饮食中的抗氧化剂（AOS）通常清除超过ROS，防止OS。此外，操作系统触发AO 防御，最终屈服于广告的进展。但是，迄今为止，涉及AO补充的临床试验已有 自相矛盾的失败，暴露了较大的知识差距，以理解哪种AO物种耗尽，时间 AO部署的过程和基本机制。 AO全反式视黄酸（ATRA），一种生物活性形式 维生素A（VA）的作用是视黄酸受体的ROS清道夫和类似马的配体 （RAR）。配体与RARS的结合对于含有视黄酸反应基因的转录调节至关重要 元素（稀有）。啮齿动物的最新证据表明，依赖年龄的稳态崩溃 在海马ATRA水平中。此外，有越来越多的证据表明转录沉默发生在AD中。 为了研究ATRA部署，我们从 验尸广告大脑。 ATRA敏感基因被下调，通过上调RAR完成 阻遏物。此外，更新了几种Hisstone脱乙酰基酶（HDAC），提供了证据 表观遗传变化。鉴于这个强大的科学前提，我们假设Atra生物利用度和 需要HDAC抑制以恢复ATRA介导的基因转录和海马依赖性 学习。因此，我们的中心假设是将维生素A补充和HDAC抑制结合在一起 （HDACI）维持海马依赖性学习和DG中的RAR敏感基因转录 比单独的HDACI有效。使用创新的多学科方法，我们将确定 将补充VA与HDAC抑制DG中RAR敏感基因的学习和转录相结合 细胞类型。 SA1检验了以下假设，即VA补充减轻了与广告相关的学习定义和多数 DG中的OMIC签名。 SA2检验了HDAC抑制减轻与广告相关的学习缺陷的假设 DG中的多摩尼克特征。 SA3检验了将VA补充和HDAC相结合的假设 抑制（VA+HDACI）协同减轻与广告相关的学习定义DG中定义和多运动特征 仅凭VA和HDACI之外。成功完成该项目将增加对异常的了解 AD期间DG中发生的转录机制。集成行为和多摩尼克数据， 项目将阐明DG中的多OMIC签名，以防止AD，可以发现新基因 DG功能所必需的，并确定对FDA批准的HDAC抑制剂的药物重新利用值。