Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer’s Disease

Article type: Review Article

Authors: Chakrabarti, Mrinmay^a | McDonald, Alexander J.^b | Will Reed, J.^c | Moss, Melissa A.^c | Das, Bhaskar C.^d | Ray, Swapan K.^{a; *}

Affiliations: [a] Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA | [b] Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA | [c] Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA | [d] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS, USA

Correspondence: [*] Correspondence to: Swapan K. Ray, PhD, Professor, Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Building 2, Room C11, 6439 Garners Ferry Road, Columbia, SC 29209, USA. Tel.: +1 803 216 3420; Fax: +1 803 216 3428; E-mail: swapan.ray@uscmed.sc.edu.

Abstract: Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer’s disease (AD). Recent studies demonstrated severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology.

Keywords: Alzheimer’s disease, amyloid-β, neuroprotection, regenerative medicine, retinoids

DOI: 10.3233/JAD-150450

Journal: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 335-352, 2016