The Therapeutic Targets of Fingolimod (FTY720) Are Involved in Pathological Processes in the Frontal Cortex of Alzheimer's Disease Patients: A Network Pharmacology Study.

Pengqi Yin,Yang Xue,Guozhong Li,Tingting Wang,Di Zhong

doi:10.3389/fnagi.2021.609679

Abstract

Background: The sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, has recently been found to reduce pathological changes in the brain tissue of Alzheimer's disease (AD) animal models, but this has yet to be verified in human brain tissue. In this study, network pharmacology methods were applied to determine the potential pharmacological mechanisms of fingolimod in the frontal cortex of AD patients.Methods: The pharmacological macromolecular targets of fingolimod and fingolimod phosphate were downloaded from SwissTarget and DrugBank. Systematic intersection analysis of the expression profiles of brain frontal cortex tissues (423 AD tissues and 266 control tissues) was performed to obtain AD-associated fingolimod targets (F-ADGs). Immune cell infiltration analysis and a primary mouse cortical culture RNA-seq drug screen database were used to identify immune-related F-ADGs and cortex-related F-ADGs. Then, the expression values of F-ADGs were correlated with the disease severity score (MMSE score) of AD patients to identify severity-related F-ADGs. We also analyzed miRNA expression microarray data in the frontal cortex of AD patients associated with disease severity to obtain severity-related F-ADG-miRNAs.Results: A total of 188 F-ADGs were detected in the frontal cortices of AD patients and were enriched in biological processes such as synaptic signaling, inflammatory response, and response to oxygen-containing compounds. Eleven immune-related F-ADGs (like FPR1, BLNK.) and 17 cortex-related F-ADGs (like ALDH1L1, DUSP1.) were detected. Other F-ADGs, such as S1PR1 and GABBR2, although not classified into the above two categories, were still predicted by bioinformatics methods to play an important role in the development of AD. Two F-ADGs (GNAQ and MMP14) and 28 miRNAs (like miR- 323a-3p, miR-181a-5p.) were found to be associated with AD severity (MMSE 0-27 group). Fifteen F-ADGs (like ALDH1L1, FPR1, and IL6.) and 46 miRNAs (like miR-212-5p, miR-93-5p.) were found to be associated with mild or moderate dementia AD patients' severity (MMSE11-22 subgroup).Conclusions: Fingolimod may affect the brain frontal cortex function of AD patients in many different ways, such as affecting immune cell infiltration, nerve cell, or glial cell function, and synaptic function. miRNAs may also be involved. ALDH1L1, FPR1, S1PR1, and GABBR2 may be core drug targets.

Highlights

Fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) modulator, is the first oral drug approved by the Food and Drug Administration (FDA) for the treatment of relapsingremitting multiple sclerosis (RRMS) (Brinkmann et al, 2010)
A total of 2,149 genes that were differentially expressed in the frontal cortices of Alzheimer’s disease (AD) patients compared to healthy controls were identified as associated genes (ADGs); 1,046 of these genes were upregulated and 1,103 were downregulated in AD patients compared to normal controls (Supplementary Material 2)
Of the 2,156 ADGs identified in the frontal cortex, 164 genes (100 upregulated and 64 downregulated) were FGs, suggesting that they are targets of fingolimod and were designated fingolimod AD-associated targets (F-ADGs)

Summary

Introduction

Fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) modulator, is the first oral drug approved by the Food and Drug Administration (FDA) for the treatment of relapsingremitting multiple sclerosis (RRMS) (Brinkmann et al, 2010). As fingolimod is a lipophilic molecule, it can cross the blood-brain barrier (BBB) (Asle-Rousta et al, 2014; Hunter et al, 2016) and has been proven to exert direct effects in the CNS of RRMS patients and in animal models of degenerative diseases of the CNS, including inhibiting microglial activation, reducing astrocyte proliferation, reducing the loss of dendritic spines, and preventing excitotoxic neuronal death (Hunter et al, 2016). The sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, has recently been found to reduce pathological changes in the brain tissue of Alzheimer’s disease (AD) animal models, but this has yet to be verified in human brain tissue. Network pharmacology methods were applied to determine the potential pharmacological mechanisms of fingolimod in the frontal cortex of AD patients

Methods

Results

Conclusion