Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street - Bldg 16, 11527, Athens, Greece.
Neuromolecular Med. 2019 Sep;21(3):227-238. doi: 10.1007/s12017-019-08558-2. Epub 2019 Jul 16.
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.
阿尔茨海默病（AD）是最常见的痴呆症病因，目前的药物治疗未能阻止疾病进展，其病因仍然不清楚。几种病理生理机制被认为与 AD 的发病机制有关，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的改变。鞘脂，如鞘氨醇-1-磷酸（S1P）和细胞内神经酰胺/S1P 平衡，在中枢神经系统生理以及 AD 的发病机制中高度涉及。FTY720/芬戈莫德，一种结构上的鞘氨醇类似物和 S1P 受体（S1PR）调节剂，目前用于治疗复发缓解型多发性硬化症（RRMS），已被证明对 AD 的进展有有益的影响。最近的体外和体内证据表明，芬戈莫德可能抑制 Aβ分泌和沉积，抑制细胞凋亡，增强脑源性神经营养因子（BDNF）的产生。此外，它调节神经炎症，防止 N-甲基-D-天冬氨酸（NMDA）-兴奋性毒性，并调节在 AD 发病机制中高度涉及的晚期糖基化终产物受体信号轴。这篇综述讨论了芬戈莫德在 AD 中新兴神经保护作用的潜在分子机制及其治疗潜力，旨在更深入地了解 AD 的发病机制，并为未来的治疗策略提供指导。
