Oxidative Stress Modifies the Levels and Phosphorylation State of Tau Protein in Human Fibroblasts (original) (raw)
Related papers
A Novel Perspective on Tau in Alzheimers Disease
Current Alzheimer Research, 2011
Mainstream thinking is dominated by the notion that the aggregation of specific proteins within neurons, and their subsequent formation into cytoplasmic and extracellular lesions, directly elicits neuronal dysfunction and death. Current dogma, for example, maintains that phosphorylated tau protein, the major component of neurofibrillary tangles, is a central mediator of disease pathogenesis. In this article, we challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress that serves a protective function. This concept provides a better understanding of the mechanisms underlying disease pathophysiology and also provides a window for therapeutic intervention.
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.
Tau-Mediated Cytotoxicity in a Pseudohyperphosphorylation Model of Alzheimer's Disease
The Journal of Neuroscience, 2002
Aggregation and increased phosphorylation of tau at selected sites ("hyperphosphorylation") are histopathological hallmarks of Alzheimer's disease (AD). However, it is not known whether the tau pathology has a primary role during neuronal degeneration. To determine the role of tau hyperphosphorylation in AD, pseudohyperphosphorylated tau (PHP-tau) that simulates disease-like permanent, high stoichiometric tau phosphorylation and mimics structural and functional aspects of hyperphosphorylated tau was expressed in neural cells. In differentiated PC12 cells, PHP-tau exhibited reduced microtubule interaction and failed to stabilize the microtubule network compared with exogenously expressed wild-type tau (wt-tau). During longer culture, PHP-tau exerted a cytotoxic effect, whereas wt-tau was neutral. PHP-tau-mediated cytotoxicity was associated with an induction of apoptotic cell death as characterized by chromatin condensation, DNA fragmentation, and caspase-3 activation in the absence of detectable protein aggregates. Furthermore, PHP-tau expression specifically sensitized the cells for other apoptotic stimuli (colchicine and staurosporine). Herpes simplex virus-mediated overexpression of PHP-tau induced degeneration associated with an induction of apoptotic mechanisms also in terminally differentiated human CNS model neurons. Partially pseudophosphorylated constructs caused an intermediate toxicity. The data provide evidence for a neurotoxic "gain of function" of soluble tau during AD as a result of structural changes that are induced by a cumulative, high stoichiometric tau phosphorylation. PHP-tauexpressing cells and organisms could provide a useful system to identify mechanisms that contribute to tau-mediated toxicity.
Tau Mediated Neurodegeneration: An Insight into Alzheimer’s Disease Pathology
Neurochemical Research
Extracellular accumulations of Aβ, hyperphosphorylation of tau and intracellular neurofibrillary tangle formation have been the hallmarks of Alzheimer’s Disease (AD). Although tau and its phosphorylation play a pivotal role in the normal physiology yet its hyperphosphorylation has been a pathological manifestation in neurodegenerative disorders like AD. In this review physiology of tau, its phosphorylation, hyperphosphorylation with the intervention of various kinases, aggregation and formation of paired helical filaments has been discussed. A brief account of various animal models employed to study the pathological manifestation of tau in AD and therapeutic strategies streamlined to counter the tau induced pathology has been given. The reasons for the failure to have suitable animal model to study AD pathology and recent success in achieving this has been included. The role of caspase cascade in tau cleavage has been emphasized. The summary of current studies on tau and the need for future studies has been accentuated.
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...
The Revitalized Tau Hypothesis on Alzheimer's Disease
Archives of Medical Research, 2010
Many hypotheses have been raised regarding the pathophysiology of Alzheimer's disease (AD). Because amyloid beta peptide (Ab) deposition in senile plaques appears as a late, nonspecific event, recent evidence points to tau phosphorylation and aggregation as the final common pathway in this multifactorial disease. Current approaches that provide evidence in favor of neuroimmunomodulation in AD and the roles of tau pathological modifications and aggregation into oligomers and filamentous forms are presented. We propose an integrative model on the pathogenesis of AD that includes several damage signals such as Ab oligomers, oxygen free radicals, iron overload, homocysteine, cholesterol and LDL species. These activate microglia cells, releasing proinflammatory cytokines and producing neuronal degeneration and tau pathological modifications. Altered and aggregated forms of tau appear to act as a toxic stimuli contributing to neurodegeneration. Recent findings provide further support to the central role of tau in the pathogenesis of AD, so this protein has turned into a diagnostic and therapeutic target for this disease. Ó
Understanding Tau phosphorylation in Alzheimer's disease
Alzheimer's disease (AD) is a fatal developing neurodegenerative disorder, associated with amyloid protein βamyloid (Aβ) and tau-protein. Insoluble β-amyloid (Aβ) deposits are found in extracellular matrix in the form of plaques of AD brain and hyper phosphorylated tau-proteins inside the cells constructs neurofibrillary tangles which leads to synaptic alterations. The cognitive defects are the major clinical manifestations in AD. Dysfunctional synaptic activity leads to ultimately nerve cell loss. Understanding the formation of tauopathies and abnormal hyperphosphorylation of tau is still milestone in AD research. The present review focus on exploration in tau pathology, tau hyperphosphorylation, role of O-GlcNAcytlation, kinase and phosphatase in tau phosphorylation.
Tau pathology in Alzheimer disease and other tauopathies
Biochimica Et Biophysica Acta-molecular Basis of Disease, 2005
Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.