Alzheimer’s disease (AD), the most common cause of dementia remains of unclear etiology with current pharmacological therapies failing to halt disease progression. Several pathophysiological mechanisms have been implicated in AD pathogenesis including amyloid-β protein (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation and alterations in bioactive lipid metabolism. Sphingolipids, such as sphingosine-1-phosphate (S1P) and intracellular ceramide/S1P balance are highly implicated in central nervous system physiology as well as in AD pathogenesis. FTY720/Fingolimod, a structural sphingosine analog and S1P receptor (S1PR) modulator that is currently used in the treatment of relapsing–remitting multiple sclerosis (RRMS) has been shown to exert beneficial effects on AD progression. Recent in vitro and in vivo evidence indicate that fingolimod may suppress Aβ secretion and deposition, inhibit apoptosis and enhance brain-derived neurotrophic factor (BDNF) production. Furthermore, it regulates neuroinflammation, protects against N-methyl-d-aspartate (NMDA)-excitotoxicity and modulates receptor for advanced glycation end products signaling axis that is highly implicated in AD pathogenesis. This review discusses the underlying molecular mechanisms of the emerging neuroprotective role of fingolimod in AD and its therapeutic potential, aiming to shed more light on AD pathogenesis as well as direct future treatment strategies.

中文翻译：

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芬戈莫德在阿尔茨海默氏病中的有益作用：分子机制和治疗潜力。

阿尔茨海默氏病（AD）是痴呆症最常见的病因，其病因尚不清楚，目前的药物疗法未能阻止疾病的进展。AD发病机制涉及多种病理生理机制，包括淀粉样β蛋白（Aβ）积累，tau过度磷酸化，神经炎症和生物活性脂质代谢改变。鞘脂（如鞘氨醇-1-磷酸酯（S1P）和细胞内神经酰胺/ S1P平衡）与中枢神经系统生理以及AD发病机理密切相关。FTY720 /芬戈莫德是一种结构性神经鞘氨醇类似物和S1P受体（S1PR）调节剂，目前已用于治疗复发缓解型多发性硬化症（RRMS），对AD进展具有有益作用。最近的体外和体内证据表明芬戈莫德可以抑制Aβ分泌和沉积，抑制细胞凋亡并增强脑源性神经营养因子（BDNF）的产生。此外，它调节神经炎症，预防Ñ甲基d天冬氨酸（NMDA）-excitotoxicity和调制受体晚期糖化终产物的信令轴是在AD发病高度牵连。这篇综述讨论了芬戈莫德在AD中新出现的神经保护作用的潜在分子机制及其治疗潜力，旨在为AD的发病机理以及未来的直接治疗策略提供更多的信息。