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.
