Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease

Abstract

Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca2+ homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g., SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.

Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

“…This data suggests that even wild-type mice experience intrinsic exposure to basal levels of ROS, due to by-products of normal physiological and metabolic processes. This led to the notion that the gradual accumulation of oxidative stress-related proteins was possible in these mice, as antioxidative and repair mechanisms are not being completely (100%) efficient [45][46][47][48][49]. Although the extent of oxidative protein damage from the frontal lobe brain region in wild- shown P. gingivalis can not only survive host's oxidative burst, but also has the ability to subvert its own oxidative stress via rubreythrin gene activation [12].…”

Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease?

“…Alternatively, aging and AD processes also lead to a gradual accumulation of oxidative stress and molecular damage suggesting existence of incomplete efficiency in anti-oxidative and repair mechanisms in the host [117].…”

Inhibition of autophagic flux by ROS promotes apoptosis during DTT-induced ER/oxidative stress in HeLa cells

“…Cells were plated into 96-well plates at a density of 1x10 4 Western blotting. After exposure to experimental conditions, expression of selected proteins in each sample was determined by western blotting.…”

“…Cells were plated in black cell culture fluorometric plates at a density of 1x10 4 cells/well in 200 µl complete medium. Each treatment was repeated in six separate wells.…”

“…During dysfunctional oxidative protein folding in the ER, misfolded proteins accumulate in the lumen accompanied by increased reactive oxygen species (ROS) production, a condition known as 'ER/oxidative stressʼ (1). Several studies have indicated that induction of ER stress is closely associated with oxidative stress during the pathogenesis of multiple human diseases such as diabetes, neurodegenerative diseases and cancer (2)(3)(4)(5). However, the role of ROS and related signals during ER stress is not well understood.…”