Retinoic Acid Signaling in Alzheimer's Disease Pathogenesis

Retinoic acid (RA), the bioactive metabolite of vitamin A, regulates gene transcription in the central nervous system via nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). This signalling axis underpins synaptic plasticity, adult neurogenesis and neuronal survival, while also modulating inflammatory and amyloid‐clearance pathways. In Alzheimer’s disease (AD), evidence indicates a decline in RA synthesis and receptor activity, contributing to aberrant processing of amyloid precursor protein through elevated β‐secretase expression and impaired non-amyloidogenic cleavage. Epigenetic repression of RA‐responsive genes exacerbates synaptic dysfunction and cognitive decline. Altered astrocyte and microglial RA metabolism further destabilises neuronal circuits, as seen in early disorganisation of the axon initial segment. Preclinical modulation of RA signalling has demonstrated restoration of hippocampal plasticity, promotion of anti-inflammatory glial states and reduction of amyloid burden. Current research aims to delineate cell-type specific RA dynamics, uncover mechanisms of transcriptional repression in AD and develop selective RAR/RXR modulators to counteract RA hyposignalling as a novel therapeutic strategy.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Retinoic Acid Signaling in Alzheimer's Disease Pathogenesis publication trend

The graph below shows the total number of articles in retinoic acid signaling in alzheimer's disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Retinoic acid: Active derivative of vitamin A that regulates gene expression via nuclear receptors.

Retinoic acid receptor (RAR): Nuclear receptor that binds retinoic acid to control transcription of target genes.

Amyloid-β (Aβ): Peptide fragment derived from amyloid precursor protein that aggregates in AD.

β-Secretase (BACE1): Enzyme that initiates amyloidogenic cleavage of amyloid precursor protein.

Astrocyte: Glial cell that supports neurons, regulates neurotransmitter uptake and modulates metabolic processes.

Axon initial segment (AIS): Proximal region of the axon crucial for action potential initiation and neuronal polarity.

Epigenetic repression: Silencing of gene expression through modifications of chromatin without altering DNA sequence.

References

1. Impact of vitamin A on the risk of mild cognitive impairment and Alzheimer's disease pathology in high‐fat‐diet–treated APP/PS1 mice. Food Frontiers (2024).
2. 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. Antioxidants (2023).
3. Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes. Cellular and Molecular Life Sciences (2024).