Oxidative Stress Biomarkers and Mitochondrial DNA Copy Number Associated with APOE4 Allele and Cholinesterase Inhibitor Therapy in Patients with Alzheimer's Disease.

Chia-Wei Liou,Chiung-Chih Chang,Meng-Han Tsai,Shih-Hsuan Chen,Tsu-Kung Lin

doi:10.3390/antiox10121971

Abstract

Studies of the oxidative/anti-oxidative status in patients with Alzheimer’s disease (AD) carrying different alleles of the apolipoprotein E (APOE) gene are currently inconclusive; meanwhile, data regarding mitochondrial DNA copy number (mtCN) remain limited. We herein determined the thiobarbituric acid reactive substances (TBARS), thiols, and mtCN in blood samples of 600 AD patients and 601 controls. A significantly higher oxidative TBARS (1.64 μmol/L), lower antioxidative thiols (1.60 μmol/L), and lower mtCN (2.34 log Delta Ct) were found in the AD cohort as compared to the non-AD cohort (1.54 μmol/L, 1.71 μmol/L, 2.46 log Delta Ct). We further identified the ε4 alleles (APOE4) and separated subjects into three groups according to the number of APOE4. A significant trend was noted in the TBARS levels of both AD and non-AD cohorts, highest in the homozygous two alleles (1.86 and 1.80 μmol/L), followed by heterozygous one allele (1.70 and 1.74 μmol/L), and lowest in the no APOE4 allele (1.56 and 1.48 μmol/L). Similar trends of lower thiols and mtCN were also found in the AD cohort. In our study of the influence of cholinesterase inhibitor therapy, we found significantly reduced TBARS levels, and elevated mtCN in AD patients receiving rivastigmine and galantamine therapy. Our study demonstrates associations between the APOE4 allele and oxidative stress biomarkers and mtCN. Using cholinesterase inhibitor therapy may benefit AD patients through attenuation of oxidative stress and manipulation of the mtCN.

Highlights

Many studies continue to investigate different etiologies of the various known forms of dementia, the cardinal pathological changes, primarily accumulations of amyloid beta and tau protein in the brain, have been demonstrated
The average mitochondrial DNA (mtDNA) copy number was noted to be significantly lower in the Alzheimer’s disease (AD) cohort than the non-AD controls (2.34 ± 0.21 vs. 2.46 ± 0.28, p < 0.001)
The higher thiobarbituric acid reactive substances (TBARS) level was found in APOE4 carriers of both the AD and non-AD cohorts, while it was more prominent in subjects carrying the homozygous allele

Summary

Introduction

Many studies continue to investigate different etiologies of the various known forms of dementia, the cardinal pathological changes, primarily accumulations of amyloid beta and tau protein in the brain, have been demonstrated. These pathological changes, and their associations with oxidative stress, are common phenomena noted in neurodegenerative disease research and are promising targets for therapeutic intervention [1]. Previous studies have demonstrated marked elevations of oxidative stress markers in patients diagnosed with Alzheimer’s disease [2]. While the underlying pathogenesis for this association remains undetermined, the induction of mitochondrial dysfunction and Antioxidants 2021, 10, 1971.

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Results

Conclusion