Conjoint hepatobiliary-enterohepatic cycles for amyloid excretion and enhancing its drug-induced clearance: a systems biology approach to Alzheimer’s disease

Abstract

The liver is the major organ responsible for metabolism of amyloid-beta, the primary toxic misfolded protein responsible for Alzheimer’s disease (AD). The present study focuses on the crucial role of liver in AD. We have developed a framework that formulates and integrates two reciprocal transport processes of amyloid, via hepato-biliary and enterohepatic circulations (EHC). Our system analysis approach shows that activating the liver X-receptor (LXR) can reduce amyloid-beta formation by increasing expression of the genes: ATP-binding-cassette-transporter (ABCA1) and Stearoyl-CoA-desaturase (SCD). Besides, activating the pregnane-X-receptor (PXR) can enhance the clearance of amyloid-beta by increasing the expression of the genes: ATP-Binding-Cassette-Superfamily-G-member-2 (ABCG2) and multidrug-resistance protein-1 (MDR1). We also identified receptor-like apical sodium-dependent bile-acid transporter (ASBT) of intestinal enterocyte, showing affinity towards amyloid-beta, suggesting amyloid-beta’s possible reuptake from intestinal contents to the systemic circulation through this receptor. Further, we have performed protein-protein interaction to evaluate the binding affinity of amyloid-beta to these receptors. Moreover, we undertook molecular docking and molecular dynamic simulation of some repurposed drugs (rifampicin, 24-hydroxycholesterols, resveratrol, cilostazol) which can target the aforesaid receptors to enhance amyloid-beta’s fecal clearance, reduce amyloid-beta formation, and prevent the reuptake of amyloid-beta from intestinal feces. Additionally, network pharmacology and synergism analysis were utilized to validate our hypothesis and identify the drug combinations, respectively. Gene-ontology investigation, network pharmacology, and consolidated pathway analysis validate the alteration of the above-mentioned gene expression profiles. Furthermore, our neuropharmacological synergism study identifies the optimal combination of the repurposed drugs. Finally, our findings on candidate drugs are substantiated by clinical-trial outcomes. Communicated by Ramaswamy H. Sarma