Open AccessQuantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option
Author(s) -
Clausznitzer Diana,
PichardoAlmarza Cesar,
Relo Ana Lucia,
Bergeijk Jeroen,
Kam Elizabeth,
Laplanche Loic,
Benson Neil,
Nijsen Marjoleen
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12351
Subject(s) - systems pharmacology , context (archaeology) , sphingolipid , disease , systems biology , medicine , computational biology , drug development , neuroscience , pharmacology , bioinformatics , drug , biology , paleontology , biochemistry
Alzheimer disease ( AD ) is a devastating neurodegenerative disorder with high unmet medical need. Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology ( QSP ) modeling provides a comprehensive quantitative framework to evaluate the relevance of biological mechanisms in the context of disease and to predict the efficacy of novel treatments. Here, we report a QSP model for AD with a particular focus on investigating the relevance of dysregulation of cholesterol and sphingolipids. We show that our model captures the modulation of several biomarkers in subjects with AD , as well as the response to pharmacological interventions. We evaluate the impact of targeting the sphingosine‐1‐phosphate 5 receptor (S1 PR 5) as a potential novel treatment option for AD , and model predictions increase our confidence in this novel disease pathway. Future applications for the QSP model are in validation of further targets and identification of potential treatment response biomarkers.