Therapeutic Targets of Fingolimod (FTY720) in the Brains of Alzheimer's Disease Patients and the Associated Biological Mechanisms: a Network Pharmacology Study

BackgroundThe sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, was recently reported to be effective in the treatment of Alzheimer’s disease (AD), but its mechanism of action remains elusive. In this study, network pharmacology methods were applied to detect the potential pharmacological mechanisms of fingolimod in the brains of these patients. MethodsThe pharmacological macromolecular targets of fingolimod and fingolimod phosphate were downloaded from Swisstarget. Systematic intersection analysis of the expression profiles of brain tissues (709 AD tissues and 534 control tissues) was performed, and AD-associated fingolimod targets (F-ADGs) in the frontal, temporal and entorhinal cortices were analysed. The Minimal Common Oncology Data Elements method was used to detect core F-ADGs. Gene function enrichment analyses of the core F-ADGs were performed. Correlation analyses were performed to identify core F-ADGs with expression levels that were associated with the severity of AD. CIBERSORTx (https://cibersortx.stanford.edu/) was used to estimate the percentages of various immune cell populations in the cortex of each AD patient. ResultsWe found the fingolimod targets S1PR1, GNG3, GNG11 and GABBR2 were simultaneously detected in all three cortical regions. The core F-ADGs in all three cortical regions were enriched in similar biological processes, such as the G protein-coupled receptor signalling pathway, synaptic transmission, and pathways related to the function of synapses, especially GABAergic synapses. Core F-ADGs in the temporal and entorhinal cortices were also enriched in functions related to calcium signalling and cholinergic synapses. Correlation analysis showed that the expression levels of 7 core F-ADGs (S1PR1, NPY, NPY2R, GNAI1, GNG5, FPR1 and GPR183) in the frontal cortex were correlated with the severity of AD. No differences in immune cell infiltration between AD patients and normal controls were observed in any of the three cortical regions. ConclusionsThe pharmacological macromolecular targets of fingolimod and fingolimod phosphate, including S1PR1, were abnormally expressed in the cortices of multiple AD patients. The pharmacological effect of fingolimod on AD may be attributed to its ability to regulate GABA synapses, calcium signalling, and cholinergic synapses, other than regulating immune cell infiltration.