Abstract
Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones—Alzheimer’s and Parkinson’s disease. Activity and toxicity of these proteins depends on the stage and form of aggregates. Excessive production of free radicals, including reactive oxygen species which lead to oxidative stress, is proven to be involved in the mechanism of pathology in most of neurodegenerative disorders. Both reactive oxygen species and misfolded proteins play a physiological role in the brain, and only deregulation in redox state and aggregation of the proteins leads to pathology. Here, we review the role of misfolded proteins in the activation of ROS production from various sources in neurons and glia. We discuss if free radicals can influence structural changes of the key toxic intermediates and describe the putative mechanisms by which oxidative stress and oligomers may cause neuronal death.
Highlights
With an increase in life expectancy, the prevalence of age-related neurodegenerative diseases has dramatically increased
We summarize the role of reactive oxygen species (ROS) and the products of oxidation in the mechanism of pathology and misfolding and the accumulation of abnormally aggregated proteins
In combination with inhibition of activity of the multidrug resistance protein 1 which mediates cellular export of glutathione conjugates, it maintains GSH-related antioxidant defense mechanisms insufficiently to protect cells against basic ROS production [92]. Another possible way of participation of mutant huntingtin protein (mHtt) in the development of oxidative stress is the decrease in expression of a transcription factor, the nuclear factor -κB (NF-κB), which mediates antioxidant and antiapoptotic signaling as a response of the endoplasmic reticulum to a stress [93]
Summary
With an increase in life expectancy, the prevalence of age-related neurodegenerative diseases has dramatically increased. Application of extracellular tau at different stages of aggregation to cortical co-cultures of neurons and astrocytes showed that only insoluble aggregates of tau are able to induce ROS production by activation of NADPH oxidase via a calcium-dependent way (Figure 2) [47] It was not (MSCs) derived from the bone marrow of patients with another form of tauopathy–progressive supranuclear palsy [52]. Considering the involvement of redox metals in the accumulation of β-amyloid, the generation of ROS β-amyloid more effectively incorporates in the membranes of astrocytes and forms pores which by complex β-amyloid-transition metal was suggested [61] It can be partially confirmed by the effects can stimulate a calcium signal because of a higher cholesterol level in these cells compared to neurons of heavy metal chelators on the β-amyloid-induced oxidative stress; it can be explained (Figure 3) [63,64]. Β-Amyloid-induced NADPH oxidase activation in combination with generation of nitric oxide
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