Retinoic acid as a therapeutic option in Alzheimer’s disease: a focus on cholinergic restoration

Abstract

Retinoic acid is a potent cell differentiating factor, which through its nuclear receptors affects a vast range of promoter sites in brain neuronal and glial cells in every step of embryonic and postnatal life. Its capacities, facilitating maturation of neurotransmitter phenotype in different groups of neurons, pave the way for its application as a potential therapeutic agent in neurodegenerative diseases including Alzheimer’s disease. Retinoic acid was found to exert particularly strong enhancing effects on acetylcholine transmitter functions in brain cholinergic neurons, loss of which is tightly linked to the development of cognitive and memory deficits in course of different cholinergic encephalopathies. Here, we review cholinotrophic properties of retinoic acid and its derivatives, which may justify their application in the management of Alzheimer’s disease and the related neurodegenerative conditions.

Keywords:

• acetyl-CoA
• Alzheimer’s disease
• cholinergic neurons
• energy metabolism
• neuroprotection
• neurotoxicity
• retinoic acid

Financial & competing interests disclosure

This work was supported by ST-57 project from Medical University of Gdańsk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Alzheimer’s disease (AD) is the most common prevalent cause of dementia in aging populations. The loss of cholinergic innervation of several cortical areas is responsible for vast range of cognitive and memory deficits in this pathology.

• Retinoic acid and its agonists may offer an alternative approach to AD management increasing expression of cholinergic and other transmitter phenotypes in respective groups of neurons yielding improvement of their neurotransmitter functions.

• Multidirectional interactions with amyloid metabolism on genomic and proteomic levels of amyloid precursor protein, disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), β-amyloid cleaving enzyme and APOE indicate that retinoic acid could be used for causative, Aβ-suppressing treatment of AD.

• Retinoic acid has no positive effects on energy metabolism, impaired by neurodegenerative conditions. Therefore, its efficient use as cholinotrophic/neurotrophic agent would require simultaneous therapy alleviating acetyl-CoA/energy deficits. That would prevent secondary neuronal injuries resulting from neurotransmission-evoked increases in energy demands.