Faculty, Staff and Student Publications

Language

English

Publication Date

3-1-2025

Journal

CPT: Pharmacometrics & Systems Pharmacology

DOI

10.1002/psp4.13296

PMID

39727246

PMCID

PMC11919260

PubMedCentral® Posted Date

12-27-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, is closely associated with Alzheimer's disease (AD). Cerebrovascular dysfunction is manifested in both T2DM and AD, and is often considered as a pathological link between the two diseases. Insulin signaling regulates critical functions of the blood-brain barrier (BBB), and endothelial insulin resistance could lead to BBB dysfunction, aggravating AD pathology. However, insulin signaling is intrinsically dynamic and involves interactions among numerous molecular mediators. Hence, a mechanistic systems biology model is needed to understand how insulin regulates BBB physiology and the consequences of its impairment in T2DM and AD. In this study, we investigated the pharmacodynamic effect of insulin on the expression of vascular cell adhesion molecule 1 (VCAM1), a marker of cerebrovascular inflammation. Intriguingly, normal insulin concentrations selectively activated the PI3K-AKT pathway, leading to decreased VCAM1 expression. However, exposure to supraphysiological insulin levels, which is present in insulin resistance, activated both PI3K-AKT and MEK-ERK pathways, and increased VCAM1 expression. We developed a mathematical model that adequately described the dynamics of various insulin signaling nodes and VCAM1 expression. Further, the model was integrated with in vitro proteomics and transcriptomics data from AD patients to simulate VCAM1 expression under pathological conditions. This approach allowed us to establish a quantitative systems pharmacology framework to investigate BBB dysfunction in AD and metabolic syndrome, thereby offering opportunities to identify specific disruptions in molecular networks that will enable us to identify novel therapeutic targets.

Keywords

Vascular Cell Adhesion Molecule-1, Insulin Resistance, Humans, Insulin, Amyloid beta-Peptides, Blood-Brain Barrier, Up-Regulation, Diabetes Mellitus, Type 2, Signal Transduction, Alzheimer Disease, Models, Biological, Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Endothelium, Vascular, Alzheimer's disease, blood–brain barrier, insulin resistance, modeling and simulation, pharmacodynamics

Published Open-Access

yes

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