Transcriptional Dysfunction in Dentate Gyrus Cell Types: Roles of Retinoic Acid Responsive Genes in Protection Against Alzheimer's Disease Pathogenesis

齿状回细胞类型的转录功能障碍：视黄酸反应基因在预防阿尔茨海默病发病机制中的作用

• 批准号: 10367173
• 负责人: John Joshua Lawrence
• 金额: $ 37.44万
• 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: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367173
• 关键词: Aging; Agonist; All-Trans-Retinol; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloidosis; Antioxidants; Autopsy; Behavior; Behavioral; Biological Markers; Brain; Cells; Chronic; DNA; Data; Electrophysiology (science); Event; Experimental Designs; Free Radicals; Functional disorder; Gene Expression; Genes; Genetic Transcription; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intake; Interneurons; J20 mouse; Knowledge; LacZ Genes; Learning; Lipids; Liver; Measures; Membrane; Memory; Memory impairment; Mitochondria; Molecular; Mus; Neuroglia; Neurons; Outcome Measure; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Performance; Play; Process; Production; Property; Proteins; Reactive Oxygen Species; Reporter; Retinoic Acid Receptor; Reversal Learning; Rodent; Role; Signal Transduction; Supplementation; Synapses; Testing; Toxic effect; Transcript; Transcriptional Regulation; Tretinoin; Up-Regulation; Vitamin A Deficiency; age related; bench to bedside; cell type; dentate gyrus; dietary; dietary manipulation; granule cell; human model; inhibitory neuron; innovation; interdisciplinary approach; mitochondrial dysfunction; mouse model; novel; oxidative damage; preservation; prevent; protective effect; public health relevance; retinoic acid receptor alpha; secondary analysis; synaptic function; theories; transcriptomics

PROJECT SUMMARY / ABSTRACT Hyperexcitability of the hippocampal dentate gyrus (DG) is associated with impaired learning in early stages of Alzheimer’s disease (AD). Causal upstream signaling mechanisms occurring within DG circuits early in AD pathogenesis remain poorly understood. The Mitochondrial Free Radical Theory of Aging proposes that mitochondria, through the production of excess reactive oxygen species (ROS), cause oxidative damage to proteins, lipids, and DNA ¾ a process termed oxidative stress (OS). Antioxidants (AOs) normally counteract this process by scavenging excess ROS, thereby preventing OS. The antioxidant all-trans retinoic acid (ATRA), the active form of retinol, has a dual role in ROS scavenging and transcriptional control of synaptic/neuronal proteins via its function as a retinoic acid receptor (RAR) agonist. Recent evidence from rodents has demonstrated an age-dependent decline in hippocampal ATRA levels due to homeostatic collapse of the liver-brain axis. We propose that ATRA depletion in the DG is an early event in AD pathogenesis, leading to excess ROS-induced damage, mitochondrial dysfunction, and reduced occupancy of RARs across DG cell types, accelerating amyloidosis, network hyperexcitability, and cognitive dysfunction. Bolstering this scientific premise, secondary analyses of human hippocampal transcriptomic data led us to discover a large number of OS- and RAR-sensitive genes dysregulated in AD brains. In preliminary studies from the J20 AD mouse model, chronic treatment with ATRA normalized behavior, prevented the formation of aberrant inhibitory circuits in the DG, and normalized a number of pathways that included RAR- and OS-sensitive genes in the DG. Therefore, our central hypothesis is that ATRA depletion induces oxidative stress and loss of transcriptional control of RAR-sensitive genes in DG cell types, which can be accelerated or delayed by bidirectionally manipulating DG ATRA levels. Using an innovative multidisciplinary approach that uniquely combines DG-dependent learning paradigms, single cell transcriptomics, and cellular/synaptic analysis in two AD mouse models, we will determine how bidirectional manipulation of ATRA levels alters transcriptional control of RAR-sensitive genes across DG cell types and impacts DG-dependent learning and cellular/synaptic function. SA1 tests the hypothesis that impaired DG-specific reversal learning is accompanied by impaired transcription of RAR-sensitive genes in DG cell types, increased OS, and mitochondrial dysfunction in two AD mouse models. SA2 tests the hypothesis that reversal learning performance, OS levels, and RAR-sensitive gene expression in DG cell types depend on dietary retinol intake in two AD mouse models. Finally, SA3 tests the hypothesis that DG circuit function depends on dietary retinol intake in two AD mouse models. Successful completion of this project will reveal novel mechanisms of DG-related learning impairments in AD and discover new AD biomarkers in specific cell types indicative of ATRA deficiency. Determining roles of retinol in protection against AD will enable rapid dissemination of knowledge from bench to bedside.

项目摘要 /摘要 海马齿状回（DG）的过度兴奋性与早期学习受损有关 阿尔茨海默氏病（AD）。 AD早期DG电路内发生的因果上游信号传导机制 发病机理仍然很少了解。衰老建议的线粒体自由基理论 线粒体通过产生过量的活性氧（ROS），对 蛋白质，脂质和DNA¾称为氧化应激的过程（OS）。抗氧化剂（AOS）通常抵消 通过清除超过ROS，这一过程可以防止OS。抗氧化剂全反式视黄酸 （ATRA）是视黄醇的活性形式，在ROS清除和转录控制中具有双重作用 突触/神经元蛋白通过其作为视黄酸受体（RAR）激动剂的功能。最近的证据 啮齿动物表明，由于体内平衡的崩溃，海马ATRA水平的年龄依赖性下降 肝脑轴的。我们建议DG中的ATRA耗竭是AD发病机理的早期事件， 导致ROS诱导的损伤过多，线粒体功能障碍以及降低RAR的占用率 DG细胞类型，加速淀粉样变性，网络过度兴奋性和认知功能障碍。加强这个 科学的前提，对人类海马转录组数据的次要分析使我们发现了一个大型 AD大脑中的OS和RAR敏感基因的数量失调。在J20 AD的初步研究中 小鼠模型，具有ATRA归一化行为的慢性治疗，阻止了异常抑制的形成 DG中的电路，并标准化了许多途径，其中包括RAR和OS敏感基因 DG。因此，我们的中心假设是ATRA耗竭诱导氧化应激和丧失 DG细胞类型中RAR敏感基因的转录控制，可以加速或延迟 通过双向操纵DG ATRA水平。使用创新的多学科方法 独特地结合DG依赖性学习范例，单细胞转录组学和细胞/突触 在两个AD鼠标模型中的分析，我们将确定双向操作ATRA水平如何改变 DG细胞类型的RAR敏感基因的转录控制，并影响DG依赖性学习和 细胞/突触功能。 SA1检验了一个假设，即DG特异性逆转学习已完成 通过DG细胞类型中RAR敏感基因的转录受损，OS和线粒体增加 两个AD鼠标模型中的功能障碍。 SA2检验了以下假设，即逆转学习绩效，OS水平， DG细胞类型中的RAR敏感基因表达取决于两个AD小鼠模型中的饮食视网膜摄入。 最后，SA3检验了DG电路功能取决于两只AD小鼠饮食中的摄入量的假设 型号。该项目的成功完成将揭示与DG相关的学习障碍的新型机制 在AD中，发现特定细胞类型的新AD生物标志物，指示ATRA缺乏症。确定角色 视黄醇在防止AD的保护方面，将能够快速传播从长凳到床边的知识。