Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern

Roberta Dal Magro,Stefano Fagioli,Francesco Mantegazza,Lorenzo Taiarol,Francesca Re,Andrea Falqui,Claudia Adriana Marrano,Alberto Casu,Beatrice Formicola,Patrizia Sommi,Valeria Cassina,Umberto Anselmi-Tamburini,Agostina Vitali

doi:10.3390/antiox10020266

Abstract

Vascular oxidative stress is considered a worsening factor in the progression of Alzheimer’s disease (AD). Increased reactive oxygen species (ROS) levels promote the accumulation of amyloid-β peptide (Aβ), one of the main hallmarks of AD. In turn, Aβ is a potent inducer of oxidative stress. In early stages of AD, the concomitant action of oxidative stress and Aβ on brain capillary endothelial cells was observed to compromise the blood–brain barrier functionality. In this context, antioxidant compounds might provide therapeutic benefits. To this aim, we investigated the antioxidant activity of cerium oxide nanoparticles (CNP) in human cerebral microvascular endothelial cells (hCMEC/D3) exposed to Aβ oligomers. Treatment with CNP (13.9 ± 0.7 nm in diameter) restored basal ROS levels in hCMEC/D3 cells, both after acute or prolonged exposure to Aβ. Moreover, we found that the extent of CNP uptake by hCMEC/D3 was +43% higher in the presence of Aβ. Scanning electron microscopy and western blot analysis suggested that changes in microvilli structures on the cell surface, under pro-oxidant stimuli (Aβ or H2O2), might be involved in the enhancement of CNP uptake. This finding opens the possibility to exploit the modulation of endothelial microvilli pattern to improve the uptake of anti-oxidant particles designed to counteract ROS-mediated cerebrovascular dysfunctions.

Highlights

IntroductionAlzheimer’s disease (AD) is the most prevalent form of dementia, accounting for
X-ray diffraction (XRD) analysis showed that all diffraction peaks corresponded to the fluoritic CeO2 crystal structure
We investigated if cell exposure to luminal or abluminal pro-oxidant stimuli differently affects the morphogenesis of microvilli, hCMEC/D3 cells were grown on transwell inserts and different concentrations of amyloid-β peptide (Aβ) oligomers were added to the basolateral side of the transwell system

Summary

Introduction

Alzheimer’s disease (AD) is the most prevalent form of dementia, accounting for. 50–75% of all 50 million people worldwide living with dementia in 2020 [1]. The etiology of AD is still unclear. The “amyloid hypothesis” has been the dominant model for several years, describing the imbalance between the production and clearance of Aβ as the causative event triggering Aβ accumulation and cognitive impairment [2,3]. Beside this hypothesis, increasing evidence recognizes the key role of cerebrovascular dysfunctions and blood–

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