Hydrogen peroxide induces transient dephosphorylation of tau protein in cultured rat oligodendrocytes (original) (raw)
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Oxidative Stress Modifies the Levels and Phosphorylation State of Tau Protein in Human Fibroblasts
Frontiers in Neuroscience
Since the tau protein is closely involved in the physiopathology of Alzheimer's disease (AD), studying its behavior in cellular models might lead to new insights on understanding this devastating disease at molecular levels. In the present study, primary cultures of human fibroblasts were established and used to determine the expression and localization of the tau protein in distinct phosphorylation states in both untransfected and tau gene-transfected cells subjected to oxidative stress. Higher immunopositivity to phospho-tau was observed in cell nuclei in response to oxidative stress, while the levels of total tau in the cytosol remained unchanged. These findings were observed in both untransfected cells and those transfected with the tau gene. The present work represents a useful model for studying the physiopathology of AD at the cellular level in terms of tau protein implications.
Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy
European Journal of Neuroscience, 2006
Truncation of tau protein and oxidative stress have been implicated as important pathogenetic events in tauopathies including Alzheimer's disease (AD). We have generated a transgenic rat model that expresses a human truncated tau protein analogous to a variant form derived from sporadic AD. We employed this model to investigate the relationship between tau protein truncation and oxidative stress. We have found that rat cortical neurons (derived from transgenic animals) that had been cultured in vitro for 16 days showed an increased accumulation of reactive oxygen species (up to 1.4-fold increase; P < 0.01) when compared to neurons derived from nontransgenic control animals. Transgene-expressing neurons treated with inducers of oxidative stress, such as glucose oxidase (GO) and buthionine sulfoximine (BSO), displayed dramatically reduced survival (31.4 ± 3.3 and 24.9 ± 3.6%, respectively; both P < 0.001) compared to neurons from control animals (79.9 ± 7.1%, survival following treatment with GO and to 98.2 ± 3.8%, survival following treatment with BSO). The number of mitochondria in processes of neurons from transgenic animals was decreased by about one-third from that present in neurons from control animals. The results reveal that expression of a human truncated variant form of tau protein leads to the accumulation of reactive oxygen species and sensitizes rat cortical neurons to cell death induced by oxidative stress. This indicates that truncation of tau may precede oxidative stress in the pathogenesis of neurodegenerative diseases such as AD and other tauopathies. These findings may have implications for therapeutic strategies aiming at prevention of neurofibrillary degeneration and cognitive decline, and identify potential new targets for drug development.
Oxidative Medicine and Cellular Longevity, 2015
Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer’s disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of theMAPTgene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxi...
Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage
Journal of Alzheimer's disease : JAD, 2009
Glutamate receptor-mediated excitotoxicity is thought to contribute to the development of Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that g...
Journal of Alzheimer's disease : JAD, 2009
Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). We investigated the effect of a truncated form of the human tau protein in the neurons of transgenic rats. Using electron paramagnetic resonance we observed significantly increased accumulation of ascorbyl free radicals in brains of transgenic animals (up to 1.5-fold increase; P < 0.01). Examination of an in vitro model of cultured rat corticohippocampal neurons revealed that even relatively low level expression of human truncated tau protein (equal to 50% of endogenous tau) induced oxidative stress that resulted in increased depolarization of mitochondria (approximately 1.2-fold above control, P < 0.01) and increases in reactive oxygen species (approximately 1.3-fold above control, P < 0.001). We show that mitochondrial damage-associated oxidative stress is an early event in neurodegeneration. Furthermore, using two common antioxidants (vitami...
Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells
Journal of Neuroscience Research, 2003
A hallmark of several neurodegenerative disorders, including Alzheimer's disease and tauopathies, is the hyperphosphorylation of the microtubule-associated protein tau. Tau phosphorylation by proline-directed and non-proline-directed protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The effect of the lipid peroxidation product acrolein on these modes of phosphorylation has been assayed. We have found that acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of tau at the site recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3 (which is also activated in response to A peptide), the acrolein-induced tau hyperphosphorylation at the same site is also due to p38 stress-activated kinase. These results support the view that oxidative stress and subsequent formation of lipid peroxidation products may contribute to tau protein phosphorylation in Alzheimer's disease and tauopathies.
Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau
PLoS ONE, 2007
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a wellcharacterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Aß load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.
Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures
Biometals, 2003
Oxidative stress phenomena have been related with the onset of neurodegenerative diseases. Particularly in Alzheimer Disease (AD), oxygen reactive species (ROS) and its derivatives can be found in brain samples of postmortem AD patients. However, the mechanisms by which oxygen reactive species can alter neuronal function are still not elucidated. There is a growing amount of evidence pointing to a role for mitochondrial damage as the source of free radicals involved in oxidative stress. Among the species that participate in the production of oxygen reactive radicals, transition metals are one of the most important. Several reports have implicated the involvement of redox-active metals with the onset of different neurodegenerative diseases such as Alzheimer's Disease (AD), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). On the other hand, our previous studies have indicated that Aβ-induced deregulation of the protein kinase Cdk5 associated with tau protein hyperphosphorylation constitute a critical pathway toward neurodegeneration. In the current paper we have shown that iron induces an imbalance in the function of Cdk5/p25 system of hippocampal neurons, resulting in a marked decrease in tau phosphorylation at the typical Alzheimer's epitopes. The loss of phosphorylated tau epitopes correlated with an increase in 4-hydroxy-nonenal (HNE) adducts revealing damage by oxidative stress. This effects on tau phosphorylation patterns seems to be a consequence of a decrease in the Cdk5/p25 complex activity that appears to result from a depletion of the activator p25, a mechanism in which calcium transients could be implicated.