ArticleAnnals of biomedical engineering2025
Cholesterol Depletion with U18666A and Methyl-β Cyclodextrin Increased Small Molecule Permeability Across Brain Microvascular Endothelial Cells.
Article in Annals of biomedical engineering, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Endothelial cytochrome P450 -derived cholesterol limits angiogenesis.Redox biology · 2026Article
- Blood-Brain Barrier Permeability Is Elevated in Type 2 Diabetes and Obesity: Associations with Cognitive Function and Metabolic Markers.Research square · 2026Article
- Dietary Lipids and Lipid-Mediated Signaling Neurovascular Unit Dysfunction: Implications for Alzheimer's and Parkinson's Diseases Pathogenesis.Molecular neurobiology · 2026Review
- Low atherogenic index of plasma is associated with spontaneous hemorrhagic transformation in acute ischemic stroke patients: a retrospective cohort study and predictive modeling based on machine learning.Lipids in health and disease · 2026Article
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Authors and funding
14 authors.
Funding
Abstract
Cholesterol is a vital component of the cell membrane and plays an essential role in mediating integral membrane protein function. Altered cholesterol regulation has been implicated in neurological diseases that are associated with blood-brain barrier breakdown. However, the role of brain barrier function in inherited disorders of cholesterol metabolism, such as Niemann-Pick disease C1 (NP-C1), remains unclear. In this study, we determined how cholesterol depletion with U18666A, a chemical inhibitor of NPC1 protein, as well as with the cholesterol-depleting agent methyl-β cyclodextrin (MβCD), impacted brain endothelial cell barrier function. We hypothesized that cholesterol depletion would decrease barrier integrity by disrupting tight junction protein continuity. To test this hypothesis, we differentiated human-induced pluripotent stem cells into brain microvascular endothelial cells (hiBMECs). We then assessed barrier integrity by quantifying trans-endothelial electrical resistance (TEER), small fluorescent molecule permeability, and tight junction continuity and protein levels. We now show that U18666A-treated hiBMECs demonstrated a 75% decrease in TEER and 9-fold increase in sodium fluorescein permeability. Similar trends were observed for hiBMECs treated with MβCD, which showed significantly lowered TEER (93% decrease) and increased sodium fluorescein permeability (20-fold higher). We also observed decreased continuity of the tight junction proteins occludin (13% lower) and claudin-5 (8% lower) as well as a 53% decrease in claudin-5 protein with U18666A treatment. Co-treating U18666A-treated hiBMECs with hydroxypropyl-β cyclodextrin (HPβCD), which releases lysosomal cholesterol, prevented these changes. Together, our results demonstrate that cholesterol is vital for hiBMEC barrier function and tight junction continuity. This study highlights the potential of therapeutics targeted to brain endothelium in NP-C1 and other cholesterol metabolism disorders.
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