Abstract
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.
Highlights
Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of Alzheimer’s disease (AD) patients
A buildup of 8-OHdG was detected in brain tissue from AD subjects, that was most prominent in mitochondrial DNA of the parietal cortex [37]. These results were confirmed by another report showing that the presence of oxidized nucleosides was inversely related to the neurofibrillary tangle content [38], further suggesting that DNA oxidation could precede lesion formation. This hypothesis was further corroborated by a study by Wang and coauthors [39] who observed higher indices of oxidation in mtDNA from neocortical regions of mild cognitive impairment (MCI) subjects compared to controls, but similar to the ones observed in AD patients, suggesting that DNA oxidation was an early event in the pathogenesis of the disease
Alzheimer’s disease (AD) is the most common age-related dementia. It is a slowly progressive and chronic neurodegenerative disorder, in which cognitive impairment is related to synapses degeneration and neuronal death occurring in the limbic system and specific regions of the cerebral cortex
Summary
Alzheimer’s disease (AD) is the most common form of dementia with a progressive course. The presence of extracellular plaques, mainly composed of amyloid beta peptide (Aβ), a 39- to 42-aminoacid residue peptide, derived from the processing of amyloid precursor protein (APP), and intraneuronal neurofibrillary tangles, consisting of tau protein aggregates, constitute, important hallmarks of the disease and serve, as a dividing line between AD and other dementias [1,2,3,4]. The etiology of AD is largely unknown, it has been hypothesized that multiple factors, including genetic components, oxidative stress, intracellular and/or extracellular accumulation of Aβ, excitotoxicity, inflammation, mitochondrial dysfunction, alteration of cytoskeleton and synapse components and neuronal loss, may play important roles in the onset of the disease [5]. One hypothesis that may account for the heterogeneous nature of AD and the fact that aging is the most obvious risk factor is the increased generation of reactive oxygen species (ROS); neurons are extremely sensitive to attack by destructive free radicals [6]
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