The Contribution of Hippocampal All-Trans Retinoic Acid (ATRA) Deficiency to Alzheimer's Disease: A Narrative Overview of ATRA-Dependent Gene Expression in Post-Mortem Hippocampal Tissue

Abstract

There is accumulating evidence that vitamin A (VA) deficiency contributes to the pathogenesis and progression of Alzheimer's disease (AD). All-trans retinoic acid (ATRA), a metabolite of VA in the brain, serves distinct roles in the human hippocampus. Agonists of retinoic acid receptors (RAR), including ATRA, promote activation of the non-amyloidogenic pathway by enhancing expression of α-secretases, providing a mechanistic basis for delaying/preventing amyloid beta (Aβ) toxicity. However, whether ATRA is actually deficient in the hippocampi of patients with AD is not clear. Here, using a publicly available human transcriptomic dataset, we evaluated the extent to which ATRA-sensitive genes are dysregulated in hippocampal tissue from post-mortem AD brains, relative to age-matched controls. Consistent with ATRA deficiency, we found significant dysregulation of many ATRA-sensitive genes and significant upregulation of RAR co-repressors, supporting the idea of transcriptional repression of ATRA-mediated signaling. Consistent with oxidative stress and neuroinflammation, Nrf2 and NfkB transcripts were upregulated, respectively. Interestingly, transcriptional targets of Nrf2 were not upregulated, accompanied by upregulation of several histone deacetylases. Overall, our investigation of ATRA-sensitive genes in the human hippocampus bolsters the scientific premise of ATRA depletion in AD and that epigenetic factors should be considered and addressed as part of VA supplementation.

Keywords: Alzheimer’s disease; aging; retinoic acid; vitamin A.

Figure 1

Distinct roles of ATRA and Nrf2-mediated AO defenses in the hippocampus proposed during normal aging and AD. (A) The non-amyloidogenic pathway and the transcription of neuroprotective proteins is promoted by ATRA suffiency, in coordination with the RXR agonist DHA. (B) The amyloidogenic pathway is promoted by ATRA deficiency. The subsequent rise in ROS causes oxidation of the Nrf2-KEAP1 complex, resulting in a compensational increase in endogenous AO defenses.

Figure 2

Theoretical detection of ATRA deficiency through gene expression analysis of human brain transcriptomics data. (A) Activation of RAR-RXR heterodimers induces increased transcription of genes that possess retinoic acid response elements (RAREs; red star). (B) In the case of ATRA sufficiency in unimpaired control brains, transcription is maintained across ATRA-sensitive genes (red stars). (C) Deficiency in ATRA leads to transcriptional repression of ATRA-sensitive genes (blue star). (D) In the case of ATRA deficiency in Alzheimer’s disease brains, transcription is decreased across ATRA-sensitive genes (blue stars).

Figure 3

Crosstalk between RAR/RXR and Nrf2 signaling. (A) In ATRA sufficiency, a reduced intracellular environment promotes binding of Nrf2 to KEAP1, facilitating degradation of Nrf2. In addition, Nrf2 is sequestered by RARα and RXR receptors. The availability of ATRA leads to sustained transcription of ATRA-sensitive genes, promoting neuroprotection. (B) In ATRA deficiency, a relative absence of antioxidants causes the generation of reactive oxygen species (ROS). Oxidative stress causes the liberation of Nrf2 from KEAP1, allowing Nrf2 to enter the nucleus. Within the nucleus, Nrf2 dimerizes with sMaf at antioxidant response elements (AREs), leading to increased transcription of endogenous antioxidants that serve to counteract ROS and ROS-induced damage. The relative absence of ATRA diminishes RAR/RXR-mediated signaling, leading to a downregulation of ATRA-sensitive genes that mediate neuroprotection.

Figure 4

Proposed effects of age-related epigenetic changes in ATRA-sensitive and Nrf2-sensitive gene transcription, and AD progression. (A) ATRA deficiency is accompanied by a co-repressor complex that includes HDAC3. The accompanying age-related upregulation of class I/II HDACs and DMNTs further ensures transcriptional silencing of both ATRA- and Nrf2-sensitive genes. (B) The activity of ATRA as a dietary exogenous AO and transcriptionally active ligand is lost in the hippocampus, thereby increasing oxidative stress and Nrf2-mediated gene expression until epigenetic changes silence the transcription of Nrf2-driven pathways, resulting in expedited ARCD and AD progression.

Figure 5

Working model of therapeutic effects of HDAC inhibitors on the activation of RAR-, PPAR-, and Nrf2-mediated gene transcription. (A) ATRA sufficiency removes the co-repressor complex and recruits histone acetylases, histone methyltransferases, and transcription factors. Therapeutic employment of a class I/II HDAC inhibitor results in an open chromatin conformation and accessible promotor region that augments the beneficial effects of ATRA sufficiency. Also, Nrf2 is transcriptionally active in circumstances of ATRA deficiency combined with a HDAC inhibitor. (B) Sufficient hippocampal ATRA concentration staves off AD progression until age-related epigenetic changes silence ATRA- and Nrf2-sensitive gene expression. (C) With ATRA insufficiency, epigenetic intervention alone will increase compensatory Nrf2-mediated AO defenses, aiding in delaying MCI and AD, but ATRA-deficiency remains, preventing the expression of ATRA-induced neuroprotective pathways. (D) HDAC inhibition, in combination with retinoid supplementation, lifts the epigenetic silencing of RAREs, PPAREs, and AREs, and allows for the activation of both ATRA- and Nrf2-responsive neuroprotective genes.