How Do Retinoids Affect Alzheimer's Disease and Can They Be Novel Drug Candidates?

Abstract

Alzheimer's disease is a chronic, neurological condition that faces many challenges in its management and therapy nowadays highlighting the importance and urgent need of researching new ways of approaching this disease. Retinoic acid and its derivatives, collectively known as the retinoids, are considered promising agents that have disease-modifying properties in affecting Alzheimer's disease. This thesis aims to address the research questions of what the role of retinoids is in Alzheimer's disease, and whether they can be used as a novel drug candidate for treating this condition. Retinoids' properties and agonistic actions on the nuclear receptors retinoic acid receptor (RAR) and retinoic X receptor (RXR) affect various pathways as well as their underlying genetic factors that compose important pathophysiological hallmarks causing the progression of Alzheimer's disease as amyloid β (Aβ) production and deposition, neurofibrillary tangle (NFT) formation and phosphorylation, and inflammatory and autoimmune responses. Retinoic acid inhibits the amplification of these pathways and modifies the disease progression in animal models, proposing a solid basis for human trials. Hence, investigating retinoids as pharmacological agents in human trials has been conducted, and several synthetic analogues have been developed to address issues concerning retinoic acid's instability and short half-life, as well as adverse drug reactions. The most prominent of these analogues is tamibarotene, a stable retinoic acid derivative with a higher half-life, higher specificity to target receptors, and fewer adverse reactions. A number of criteria that explain what a novel drug candidate should have when managing Alzheimer's disease have been formulated, and which also explain why most novel drug candidates other than retinoic acid have failed in achieving clinical results. Most of these candidates share one common trait which is a single-target approach in targeting disease pathways. This means that when administering these agents, their actions are to target a single disease-causing pathway at a time but do not affect other pathways. On the other hand, tamibarotene is a novel drug candidate that targets a range of pathways at once and provides a more comprehensive approach in its pharmacological actions.