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