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bioRxiv · 10.1101/2024.08.28.610108

Altered Copper Transport in Oxidative Stress-Dependent Brain Endothelial Barrier Dysfunction Associated with Alzheimer's Disease

Hossain, M. S.·Das, A.·Rafiq, A. M.·Deak, F.·Bagi, Z.·Outlaw, R.·Varadarajan, S.·Yamamoto, M.·Kaplan,, J. H.·Ushio-Fukai, M.·Fukai, T.
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Abstract

Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimers Disease (AD), which is characterized by beta-amyloid (A{beta}) 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 A{beta}42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A and/or ATP7B were downregulated in the hippocampus of AD mouse models, and in A{beta}42-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, A{beta}42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function in hBMEC (measured by transendothelial electrical resistance), and tyrosine phosphorylation of VE-cadherin 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 A{beta}42 promotes ROS-dependent brain endothelial barrier dysfunction and VE-Cadherin 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. HighlightsO_LIUpregulation of the Cu importer CTR1 and downregulation of the Cu exporter ATP7A in the hippocampus of AD mouse models C_LIO_LIA{beta}42 increases CTR1 expression while reduces ATP7A and ATP7B levels in human brain microvascular ECs. C_LIO_LIA{beta}42 triggers increased reactive oxygen species (ROS) production in human brain microvascular ECs through a CTR1- and Cu-dependent manner. C_LIO_LIA{beta}42 induces endothelial barrier dysfunction in human brain microvascular ECs through a CTR1-Cu-ROS-pendent manner. C_LI

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Hossain, M. S., Das, A., Rafiq, A. M., Deak, F., Bagi, Z., Outlaw, R., Varadarajan, S., Yamamoto, M., Kaplan,, J. H., Ushio-Fukai, M., Fukai, T.. 2024-08-29. Altered Copper Transport in Oxidative Stress-Dependent Brain Endothelial Barrier Dysfunction Associated with Alzheimer's Disease. https://doi.org/10.1101/2024.08.28.610108

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