Oxidant/Antioxidant Imbalance in Alzheimer's Disease: Therapeutic and Diagnostic Prospects

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society. Compelling evidence demonstrates that molecular change characteristics for AD, such as oxidative stress and amyloid β (Aβ) oligomerization, precede by decades the onset of clinical dementia and that the disease represents a biological and clinical continuum of stages, from asymptomatic to severely impaired. Nevertheless, the sequence of the early molecular alterations and the interplay between them are incompletely understood. This review presents current knowledge about the oxidative stress-induced impairments and compromised oxidative stress defense mechanisms in AD brain and the cross-talk between various pathophysiological insults, with the focus on excessive reactive oxygen species (ROS) generation and Aβ overproduction at the early stages of the disease. Prospects for AD therapies targeting oxidant/antioxidant imbalance are being discussed, as well as for the development of novel oxidative stress-related, blood-based biomarkers for early, noninvasive AD diagnostics.

Figure 1

Escalating signs of the antioxidant/oxidant imbalance detected in whole blood during the AD progression. The figure schematically presents the progressive impairments in the oxidative stress defense mechanisms during the progression from mild cognitive impairment (MCI) towards severe AD. These correspond to the elevation in the oxidative stress markers. The green-orange-red colour scale corresponds to healthy stage-MCI-AD progression. AD: Alzheimer's disease; MCI: mild cognitive impairment; ACO2: aconitase 2; GR: glutathione reductase; GSH/GSSG: reduced/oxidized glutathione pool; 4-HNE: 4-hydroxynonenal; NOS-2: nitric oxide synthase 2; 3-NT: 3-nitrotyrosine; 8OHdG: 8-oxo-2′-deoxyguanosine; SOD: superoxide dismutase; UCP-1: uncoupling protein 1.