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

Transcriptional Dysfunction in Dentate Gyrus Cell Types: Roles of Retinoic Acid Responsive Genes in Protection Against Alzheimer's Disease Pathogenesis is sponsored by National Institutes of Health (NIH). This opportunity supports mission-aligned projects and measurable outcomes.

Transcriptional Dysfunction in Dentate Gyrus Cell Types: Roles of Retinoic Acid Responsive Genes in Protection Against Alzheimer's Disease Pathogenesis Project Number 5R01AG071859-05 Former Number 1R01AG071859-01 Contact PI/Project Leader LAWRENCE, JOHN JOSHUA 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.

Public Health Relevance Statement PUBLIC HEALTH RELEVANCE STATEMENT (PROJECT NARRATIVE) There is growing evidence that pathological accumulation of toxic reactive oxygen species (ROS) is an early event in the hippocampal dentate gyrus (DG) of patients with Alzheimer’s disease.

This proposal tests the hypothesis that depletion of the antioxidant all-trans retinoic acid (ATRA) in the DG promotes ROS toxicity, mitochondrial dysfunction, and transcriptional dysregulation of ATRA-sensitive genes.

Combining novel AD mouse model crosses, single cell transcriptomics, and electrophysiology, this proposal investigates roles of RA in preserving DG-specific learning, DG circuit function, and transcription of RA-sensitive genes across DG cell types. No NIH Spending Category available.

Acceleration Aging Agonist All-Trans-Retinol Alzheimer's Disease Alzheimer's disease biomarker Alzheimer's disease brain Alzheimer's disease model Alzheimer's disease patient 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 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 Oxidative Stress Induction Pathogenesis Pathologic Pathway interactions 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 Upregulation Vitamin A Deficiency age related age related decline 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 secondary analysis synaptic function theories transcriptomics [Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]](https://public.

csr. nih. gov/StudySections/StandingStudySections) Administering Institutes or Centers National Institute on Aging Assistance Listing Number Project Funding Information for 2026 No Sub Projects information available for 5R01AG071859-05 Publications are associated with projects, but cannot be identified with any particular year of the project or fiscal year of funding.

This is due to the continuous and cumulative nature of knowledge generation across the life of a project and the sometimes long and variable publishing timeline. Similarly, for multi-component projects, publications are associated with the parent core project and not with individual sub-projects.

No Publications available for 5R01AG071859-05 No Patents information available for 5R01AG071859-05 The Project Outcomes shown here are displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed are those of the PI and do not necessarily reflect the views of the National Institutes of Health. NIH has not endorsed the content below.

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