Beneficial Effects of Fingolimod in Alzheimer's Disease
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Greece
Beneficial Effects of Fingolimod in Alzheimer's Disease: Molecular Mechanisms and Therapeutic Potential
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.