Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease.

Autor: Hossain MS; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912., Das A; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30901, United States of America., Rafiq AM; Department of Neuroscience and Regenerative Medicine, Medical College of, Georgia, at Augusta University, Augusta, GA 30912., Deák F; Department of Neuroscience and Regenerative Medicine, Medical College of, Georgia, at Augusta University, Augusta, GA 30912., Bagi Z; Department of Physiology, Medical College of, Georgia, at Augusta University, Augusta, GA 30912., Outlaw R; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912., Sudhahar V; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30901, United States of America., Yamamoto M; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912., Kaplan JH; Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, IL 60607, United States of America., Ushio-Fukai M; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912; Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, GA 30912. Electronic address: mfukai@augusta.edu., Fukai T; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912; Department of Pharmacology and Toxicology, Medical College of, Georgia, at Augusta University, Augusta, GA 30912; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30901, United States of America. Electronic address: tfukai@augusta.edu.
Jazyk: angličtina
Zdroj: Vascular pharmacology [Vascul Pharmacol] 2024 Sep 22; Vol. 157, pp. 107433. Date of Electronic Publication: 2024 Sep 22.
DOI: 10.1016/j.vph.2024.107433
Abstrakt: Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer's Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A was downregulated in the hippocampus of AD mouse models and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, in cultured hBMECs, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function (measured by transendothelial electrical resistance), and tyrosine phosphorylation of CDH5 were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and CDH5 phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.
Competing Interests: Declaration of competing interest The author (MUF) is an Editorial Board Member for Vascular Phar macology and was not involved in the editorial review or the decision to publish this article. All other authors (MSH, AD, AMR, FD, ZB, RO, VS, MY, JHK, TF) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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