Therapeutic insights elaborating the potential of retinoids in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is perceived with various pathophysiological characteristics such oxidative stress, senile plaques, neuroinflammation, altered neurotransmission immunological changes, neurodegenerative pathways, and age-linked alterations. A great deal of studies even now are carried out for comprehensive understanding of pathological processes of AD, though many agents are in clinical trials for the treatment of AD. Retinoids and retinoic acid receptors (RARs) are pertinent to such attributes of the disease. Retinoids support the proper functioning of the immunological pathways, and are very potent immunomodulators. The nervous system relies heavily on retinoic acid signaling. The disruption of retinoid signaling relates to several pathogenic mechanisms in the normal brain. Retinoids play critical functions in the neuronal organization, differentiation, and axonal growth in the normal functioning of the brain. Disturbed retinoic acid signaling causes inflammatory responses, mitochondrial impairment, oxidative stress, and neurodegeneration, leading to Alzheimer's disease (AD) progression. Retinoids interfere with the production and release of neuroinflammatory chemokines and cytokines which are located to be activated in the pathogenesis of AD. Also, stimulating nuclear retinoid receptors reduces amyloid aggregation, lowers neurodegeneration, and thus restricts Alzheimer's disease progression in preclinical studies. We outlined the physiology of retinoids in this review, focusing on their possible neuroprotective actions, which will aid in elucidating the critical function of such receptors in AD pathogenesis.

Keywords: RARS; RXRS; neuroinflammation; neuroplasticity; neurotransmission; retinoids.

FIGURE 1

Schematic representation of the transport and signaling pathways of retinoic acid from retinol via the activity of alcohol dehydrogenase (ALDH) and degradation through CYP26. Retinoic acid mediates its activity by interacting with the RA receptors in RA responsive cell. RBP, Retinol binding protein; RARE, Retinoic acid response element.

FIGURE 2

The overactivation of the ß- and Γ-secretases complexes may lead to the formation of Aß fibrils which successively leads to the generation of amyloid-ß plaques and neuroinflammation by activating the pro-inflammatory cytokines like TNF and IL. Such type of overactivation can be inhibited by the activity of retinoids like retinoic acid (RA). TNF-α, Tumour necrosis factor-alpha; IL, interleukins; Aß, amyloid beta; APP, Amyloid precursor protein; C99, carboxyl fragment 99.

FIGURE 3

A model of retinoic acid signaling in the central nervous system, which plays an important role in the stimulation of transcriptional machinery to modulate the cholinergic neurotransmission through the production of choline-acetyl transferase mRNA and acetylcholine on the interaction of retinoic acid with its nuclear receptors. CHAT, choline acetyltransferase; VACHT, vesicular acetylcholine transporter; acetyl coA, acetyl coenzyme A; ACHE, acetylcholinesterase enzyme.

FIGURE 4

A schematic framework of activity-dependent retinoid generation in neurons. Appropriate synaptic transmission inhibits RA production in a Ca²⁺-dependent manner by activating glutamate receptors and L-type Ca²⁺channels. Limiting glutamate receptors or L-type Ca²⁺ channels reduces dendritic L-type Ca²⁺ intake and de-represses retinoid production, allowing AMPARs to be translated and inserted synaptically neural cells to increase the calcium influx. ALDH, alcohol dehydrogenase; AMPA, amino-hydroxy-methyl-isoxazolepropionic acid receptor; NMDA, N-methyl-D-aspartate receptor; VGCC, volatge gated calcium channel; RAR/RXR, retinoic acid receptors.