Oxidative protein damage in cells engaged in β-amyloidosis is related to apoE genotype

Abstract

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease. The reduced antioxidant defense in epsilon4 carriers is suggested to contribute to beta-amyloidosis. We found that oxidative stress induced by treatment with Fe2+ ions raised more protein carbonyls in vascular smooth muscle cells isolated from human brains with apoE genotype epsilon4/epsilon4 than with 3epsilon/epsilon3 and epsilon3/epsilon4. Antioxidant vitamin E prevented formation of carbonyls but not in cells with genotype epsilon4/epsilon4. Treatment with Fe2+ ions induced cellular accumulation of amyloid-beta protein (Abeta)-immunoreactive material that co-localized with heme oxygenase, a marker of oxidative stress, and apoE. We hypothesize that the damage caused by oxidation in epsilon4/epsilon4 carriers facilitates development of beta-amyloidosis.

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models

“…Biochemical, cell biological and transgenic animal studies have suggested several mechanisms to explain apoE4's contribution to the pathogenesis of AD. These include the modulation of the deposition and clearance of Aβ and the formation of plaques [31,33,34,76,86,[128][129][130][131][132][133], impairment of the antioxidative defence system [134][135][136], dysregulation of the neuronal signalling pathways [137][138][139], disruption of cytoskeletal structure and function [113,114,120], increased phosphorylation of tau and the formation of NFTs [56,140], impairment of glucose metabolism and mitochondrial integrity and function [59,[97][98][99][100][101][102][103][104][105][106][107][108][109][110][111] and impairment of GABAergic interneuron function and hippocampal neurogenesis [88,126]. However, the mechanisms of these apoE4-mediated effects are still poorly understood.…”

Oxidative Stress, Mitochondrial Dysfunction, and Stress Signaling in Alzheimers Disease

“…Additionally, post mortem studies indicate that apoptotic biochemical cascades are activated in vulnerable neuronal populations in AD [26,27]. The fact that all of the risk factors for disease including age [28], apolipoprotein E genotype [29,30], and amyloid-β protein precursor and presenilin mutations [31][32][33][34], directly cause alterations in redox homeostasis, leading to a compensatory increase in Aβ [35] emphasizes the significance of oxidative stress in AD pathogenesis…”

Die Bedeutung des Pyroglutamat-Abeta-Oligomer-Blutplasmaspiegels und des Apolipoprotein-E-Genotyps bei der Alzheimer-Krankheit

“…Die zellulären Effekte des E4-Phänotyps sind vor allem eine Einschränkung des antioxidativen Abwehrsystems (Miyata und Smith 1996;Lauderback et al 2002;Mazur-Kolecka et al 2002), eine Dysregulation neuronaler Signalwege (Herz und Beffert 2000) und eine Unterbrechung zytoskelettaler Struktur und Funktion (Nathan et al 1994;Bellosta et al 1995;Nathan et al 1995).…”