Are Retinoids a Promise for Alzheimer’s Disease Management?

M.      R. Carratu; C.      Marasco; A.      Signorile; C.      Scuderi; L.      Steardo

Abstract

Retinoids regulate several physiological and pathological processes through the interaction with nuclear receptors. Retinoidassociated signaling which plays an essential role in neurodevelopment appears to remain active in the adult central nervous system (CNS), thus assuming a high significance in the context of neurodegeneration, and indeed retinoid analogs are thought to be promising therapeutic agents for the treatment of neurodegenerative disorders. The ability of retinoids to exert antioxidant effects, inhibit amyloid-β (Aβ) deposits and likely Aβ-induced mitochondrial dysfunction, tau hyperphosphorylation, Aβ-induced IL6 production and neuroinflammation, increase survival in hippocampal neurons, and reverse cognitive deficits in animal models of Alzheimer’s disease (AD) is discussed. Although retinoids with their multi-target activity are revealing to be promising for management of AD which is a multifaceted biochemical phenomenon, timing as well as appropriate dosage and safety remain, however, a challenge. The end-stage lesions, namely senile plaques and neurofibrillary tangles, are, at present, considered an adaptive response to oxidative stress underlying AD, thus paradoxically late administration of retinoids could even suppress a protective mechanism by inhibiting Aβ deposits.

Keywords: Alzheimer’s disease, retinoid, cognitive decline, oxidative stress, amyloid cascade, secretases, mitochondrial dysfunction, neuroinflammation, cerebral microvessels, neuroprotection, therapeutic strategy