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 海马齿状回(DG)与学习和记忆密切相关，是学习和记忆的脆弱区域。 与年龄相关的认知障碍(ARCD)和阿尔茨海默病(AD)。因果上行信号 导致AD的机制仍然知之甚少。在整个寿命中，过量的活性氧物种(ROS) 积累，对蛋白质、脂质和DNA造成氧化损伤。这一过程被称为氧化应激。 (OS)。饮食中的抗氧化剂(AO)通常清除过量的ROS，防止OS。此外，操作系统还会触发AO 防御，最终导致AD进展。然而，到目前为止，涉及AO补充的临床试验已经 矛盾的是失败了，暴露了在理解哪些AO物种正在枯竭方面的巨大知识鸿沟，时间 氧合酶耗竭的过程和潜在的机制。全反式维甲酸(ATRA)，一种生物活性形式 维生素A(VA)，作为ROS清除剂和维甲酸受体的激素样配体具有双重作用 (RAR)。与视黄酸受体的配基结合对维甲酸反应基因的转录调控至关重要 元素(稀有)。最近来自啮齿动物的证据表明，与年龄相关的内环境平衡崩溃 在海马区ATRA水平。此外，越来越多的证据表明，转录沉默发生在AD中。 为了研究全反式维甲酸的耗竭，我们对来自 死后AD的大脑。全反式维甲酸敏感基因下调，伴随RAR上调 抑制者。此外，一些组蛋白脱乙酰酶(HDAC)表达上调，为 表观遗传变化。鉴于这一强有力的科学前提，我们假设ATRA的生物利用度和 需要抑制HDAC来恢复ATRA介导的基因转录和海马区依赖 学习。因此，我们的中心假设是将补充维生素A和抑制HDAC结合起来 (HDACi)在DG More中维持海马依赖的学习和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 维生素A联合HDAC抑制DG大鼠学习记忆和RAR敏感基因转录 单元类型。SA1验证了补充维生素A可减轻AD相关学习障碍和多项功能障碍的假说 DG中的OMIC签名。SA2验证了HDAC抑制可缓解AD相关学习障碍的假说 和DG中的多组签名。SA3检验了维生素A补充剂和HDAC相结合的假设 抑制(VA+HDACi)协同减轻AD相关的学习缺陷和DG中的多组特征 仅限于退伍军人管理局和HDACi。这个项目的成功完成将增加对反常的认识 阿尔茨海默病期间DG的转录机制。整合了行为数据和多组学数据， 该项目将阐明DG中预防AD的多个基因组签名，使新基因的发现成为可能 DG功能所必需的，并确定FDA批准的HDAC抑制剂的药物再用途的价值。