Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β

TL;DR

This study shows that antioxidants Trolox and methazolamide can protect brain endothelial cells from oxidative damage caused by amyloid-beta oligomers linked to Alzheimer's disease.

Contribution

The study identifies specific antioxidants that reduce oxidative stress caused by both sporadic and familial forms of amyloid-beta oligomers in microvascular endothelial cells.

Findings

Amyloid-beta oligomers induce oxidative stress markers like lipid peroxidation and protein carbonylation in endothelial cells.

Antioxidants Trolox and methazolamide significantly reduce ROS production and oxidative stress caused by amyloid-beta.

Oligomeric amyloid-beta forms are heterogeneous and trigger distinct conformational antibody responses.

Abstract

Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer’s disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21–23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.

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