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