Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics

Abstract

Alzheimer disease (AD) is a neurodegenerative disease with many known pathological features, yet there is still much debate into the exact cause and mechanisms for progression of this degenerative disorder. The amyloid-beta (Aβ)-induced oxidative stress hypothesis postulates that it is the oligomeric Aβ that inserts into membrane systems to initiate much of the oxidative stress observed in brain during the progression of the disease. In order to study the effects of oxidative stress on tissue from patients with AD and amnestic mild cognitive impairment (MCI), we have developed a method called redox proteomics that identifies specific brain proteins found to be selectively oxidized. Here, we discuss experimental findings of oxidatively modified proteins involved in three key cellular processes implicated in the pathogenesis of AD progression: energy metabolism, cell signaling and neurotransmission, as well as the proteasomal degradation pathways and antioxidant response systems. These proteomics studies conducted by our laboratory and others in the field shed light on the molecular changes imposed on the cells of AD and MCI brain, through the deregulated increase in oxidative/nitrosative stress inflicted by Aβ and mitochondrial dysfunction.

Association of Plasma DPP4 Activity With Mild Cognitive Impairment in Elderly Patients With Type 2 Diabetes: Results From the GDMD Study in China

“…Even at the stage of MCI, damage inflicted by oxidative stress to key proteins leads to deficiencies in systems important to the brain, such as neurotransmitter release, cell signaling, energy metabolism, and the proteasome, which might lead to the progression and pathogenesis of cognitive decline (7). In addition, oxidative parameters in the circulation were also higher in patients from MCI groups than in the control group (23,24).…”

“…Chronic hyperglycemia is implicated, perhaps by promoting the development of cerebral microvascular disease (6). Inflammation and oxidative stress also appear to be involved in the pathogenesis of cognitive decline (5,7). These two factors form a vicious cycle that accelerates brain injury and cognitive impairment.…”

Multitarget trehalose-carnosine conjugates inhibit Aβ aggregation, tune copper(II) activity and decrease acrolein toxicity

“…[72] By-products of lipid peroxidation such as ACR accumulates in different regions of the brain of AD patients affected by mild cognitive impaired (MCI). [73] This aldehyde causes cell death in neuronal primary culture from hippocampus, inhibits mitochondrial activity and modulates tau phosphorylation through different pathways. [74] Recently, protein conjugated ACR found in the cerebrospinal fluid has been proposed as a biomarker to distinguish MCI from AD.…”

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

“…Harmine, an endogenous compound from the breakdown of tryptophan is also an inhibitor (He et al, 2015). In the last 5 years most inhibitor development has focused on maintaining a relatively equal inhibitory activity against AChE and BChE with IC 50 values below μmolar concentrations in a compound that also acts on other targets such as MAO (see below), antioxidant, metal chelation, and preventing protein aggregation (for reviews see: León et al, 2013; Swomley and Butterfield, 2015). Many groups have synthesized and tested a variety of combinations.…”

“…The most obvious physiological symptoms are the loss of neurons in Alzheimer's Disease (AD) and Parkinson's Disease (PD) with the consequently lower neurotransmitter levels, and the formation of protein aggregates in all forms of neurodegeneration. These observations provided the primary targets to date, namely enzymes catalyzing neurotransmitter breakdown (cholinesterases, ChE; monoamine oxidases, MAO; catechol-O-methyltransferase, COMT), prevention of production of amyloid beta (Aβ) by beta-secretase, of protein aggregation, and of oxidative damage known to stress cells to the point of apoptosis (Guzior et al, 2015; Swomley and Butterfield, 2015). Intervention in the potentially damaging outcomes of oxidation stress either by means of upstream (prevention of free radical generation) or downstream (free radical scavenging) antioxidant pathways helps preserve neurons and slow neurodegeneration (Uttara et al, 2009).…”