Oxidative stress and mitochondrial dysfunction in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) exhibits extensive oxidative stress throughout the body, being detected peripherally as well as associated with the vulnerable regions of the brain affected in disease. Abundant evidence not only demonstrates the full spectrum of oxidative damage to neuronal macromolecules, but also reveals the occurrence of oxidative events early in the course of the disease and prior to the formation of the pathology, which support an important role of oxidative stress in AD. As a disease of abnormal aging, AD demonstrats oxidative damage at levels that significantly surpass that of elderly controls, which suggests the involvement of additional factor(s). Structurally and functionally damaged mitochondria, which are more proficient at producing reactive oxygen species but less so in ATP, are also an early and prominent feature of the disease. Since mitochondria are also vulnerable to oxidative stress, it is likely that a vicious downward spiral involving the interactions between mitochondrial dysfunction and oxidative stress contributes to the initiation and/or amplification of reactive oxygen species that is critical to the pathogenesis of AD.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Oxidative stress is primarily caused by excessive ROS produced by impaired electron transport, endoplasmic reticulum stress, and peroxisomes (Fig. 2) [24,83,98,101,102]. Decreases in enzymatic antioxidant defense capacity, including multiple superoxide dismutases (SOD), peroxiredoxins, and glutathione [103,104], further exacerbates oxidative damage [83,85,98,100].…”

“…Decreases in enzymatic antioxidant defense capacity, including multiple superoxide dismutases (SOD), peroxiredoxins, and glutathione [103,104], further exacerbates oxidative damage [83,85,98,100]. Oxidative damage of multiple cellular components has been documented in both preclinical models of AD and in persons with the disease [102,105]. Key enzymes involved in mitochondrial function, such as PDH and α-ketoglutarate dehydrogenase, are often targeted by ROS, leading to deceased enzyme activity and decreased efficiency of mitochondrial electron transport (Fig.…”

“…In AD, elevated oxidative stress is detectable in the form of lipid peroxides, 8-oxoguanine, and other oxidized proteins [107][108][109][110]. In parallel, oxidative stress has been demonstrated to increase Aβ production in vitro and in vivo [102,109]. Several candidates have been proposed to prevent or reduce oxidative damage, and have been investigated as treatments for AD (Table 3).…”

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

“…Metabolic stress is the hypermetabolic catabolic response to severe injury or disease, and the modern notion of metabolic stress also includes disturbances in proteostasis and the activation of signaling pathways that mediate cellular stress. 3 Metabolic stress has been demonstrated to induce a number of cellular process impairments such as mitochondrial changes, reduced metabolic rate, radical oxygen species ( b AU4 ROS) produced by mitochondria, 4 and finally, the inflammation process, which can impact on the health of individuals, including the central nervous system (CNS). 5 Feeding mice with a high-fat (HF) diet induced glucose metabolism disturbances with increases in weight and insulin resistance.…”

Captopril and Valsartan May Improve Cognitive Function Through Potentiation of the Brain Antioxidant Defense System and Attenuation of Oxidative/Nitrosative Damage in STZ-Induced Dementia in Rat

“…9,14 Additionally, enhancement of NO production in brain during AD induces nitrosative damage and combination of NO with ROS leads to formation of very toxic compound of peroxynitrite (ONOO -), which yields to the protein nitrotyrosination and cell death. 10,14,15 Previous reports have demonstrated the possibility that treatment with antihypertensive RAS inhibitors prevent the impairment of cognitive performance. 16,17 Preclinical and clinical studies confirm involvement of the brain RAS in memory dysfunction.…”