UNIPROT:P10636 - FACTA Search

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Query: UNIPROT:P10636 (tau protein)
5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.
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PMID:Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease. 1093 65

Subcellular mRNA localization, a fundamental mechanism for regulating gene expression, leads to local protein translation that results in the generation of neuronal cell polarity. In this study, we have used P19 embryonic carcinoma cells, which are amenable to transfection, and selection of clonal stable cell lines that are not overexpressing the constructs. We identified the 3' untranslated region (3'UTR) tau axonal localization signal and examined its effect on tau protein localization in nondifferentiated and neuronally differentiated P19 cells. Using GFP-tagged tau constructs combined with in situ hybridization analysis, we demonstrated colocalization of the targeted tau mRNA and its translated protein in the axon and growth cone. Absence of or mutation in the 3'UTR axonal targeting region of tau mRNA resulted in suppression of tau mRNA localization, and both tau mRNA and tau protein remained in the cell body. Swapping between the 3'UTR tau mRNA axonal localization signal and the 3'UTR MAP2 mRNA dendritic targeting signal proved that the localization of the proteins into the axon or dendrites depends on the specific 3'UTR targeting signals. Moreover, the identification of ribosomal proteins in the axon lends further support to the presence of protein synthetic machinery in the axons, a prerequisite for local translation. It is suggested therefore that the P19 cell system can be used to analyze mutations that affect mRNA transport and local translation and that it has the potential of being used to examine the onset of the neuronal differentiation process.
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PMID:Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. 1151 47

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.
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PMID:The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. 1558 21

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.
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PMID:Tau pathology in Alzheimer disease and other tauopathies. 1561 38

The aim of this study was to explore the regulatory effects of cytokines, such as EGF and bFGF, on expression of the neural-specific molecules tau and MAP2 mRNA in mononuclear cells (MNCs) derived from human umbilical cord blood (UCB). Phenotypic changes were monitored by inverse phase-contrast microscopy. Tau and MAP2 mRNA were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Tau and MAP2-positive cells were determined by immunocytochemistry. The expression of tau mRNA was negative in uncultured cells, but MAP2 mRNA was positive; in cultured cells, tau protein mRNA expression was positive, MAP2 mRNA expression was upregulated by EGF+bFGF, EGF and bFGF compared to the control group (no cytokines). EGF+bFGF had a greater effect on MAP2 mRNA expression than EGF or bFGF alone. The same upregulatory tendency was noted for tau mRNA expression. It is concluded that MNCs derived from human UCB cells may express some neural specific molecules that can be upregulated by cytokines, especially EGF and bFGF together.
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PMID:Effects of EGF and bFGF on expression of microtubule-associated protein tau and MAP-2 mRNA in human umbilical cord mononuclear cells. 1577 13

Alzheimer disease (AD) and related tauopathies are all characterized histopathologically by neurofibrillary degeneration. The neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAP1 and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. The state of phosphorylation of a phosphoprotein is the function of the activities of protein kinases and as well as of protein phosphatases that regulate the level of phosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. A decrease in PP-2A activity results in the abnormal hyperphosphorylation of tau not only by decreased dephosphorylation of tau but also by stimulating the activities of tau kinases like CaMKII, PKA and MAP kinases which are regulated by PP-2A. Thus, the abnormal hyperphosphorylation can be inhibited both by inhibition of the activity/s of a tau protein kinase and as well as by restoration of the activity/s of a tau protein phosphatase. The development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to inhibit the progression of AD and related tauopathies.
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PMID:Pharmacological approaches of neurofibrillary degeneration. 1597 99

The hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer's disease (AD) and of the associated cognitive decline. EMK1 (MARK2) is a serine/threonine kinase which phosphorylates tau and MAP2. An involvement of this kinase in memory functions is not established. We used a behavioral approach to study the phenotype of EMK1-null mice (EMK1-KO) as a possible model of MAP2/tau altered phophorylation. Compared to wild type mice, EMK1-KO mice did not differ in non-cognitive aspects of behavior, such as locomotion in activity cages, or anxiety in the elevated plus maze. However, they exhibited lower performance in the first stage of acquisition of a hippocampal-dependent spatial learning, as assessed in a radial water maze, although, they acquired the task with repeated training. They were again found to be impaired on re-learning a new platform position. In addition, they exhibited poor long-term retention performance. These data underline the importance on both early memory processes and long-term retrieval, of the dynamic instability of microtubules generated by the phosphorylation of MAPs.
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PMID:Impairment of spatial learning and memory in ELKL Motif Kinase1 (EMK1/MARK2) knockout mice. 1719 7

It has been recently shown that the Alzheimer's disease (AD) pathogenic peptide amyloid beta(1-42) (Abeta(1-42)) binds to the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) with high affinity and the alpha7nAChR and Abeta(1-42) are both found colocalized in neuritic plaques of human brains with AD. Moreover, the intraneuronal accumulation of Abeta(1-42) was shown to be facilitated by its high-affinity binding to the alpha7nAChR, and alpha7nAChR activation mediates Abeta-induced tau protein phosphorylation. To test the hypothesis that alpha7nAChRs are involved in AD pathogenesis, we used a transgenic mouse model of AD overexpressing a mutated form of the human amyloid precursor protein (APP) and lacking the alpha7nAChR gene (APPalpha7KO). We have shown that, despite the presence of high amounts of APP and amyloid deposits, deleting the alpha7nAChR subunit in the mouse model of AD leads to a protection from the dysfunction in synaptic integrity (pathology and plasticity) and learning and memory behavior. Specifically, APPalpha7KO mice express APP and Abeta at levels similar to APP mice, and yet they were able to solve a cognitive challenge such as the Morris water maze test significantly better than APP, with performances comparable to control groups. Moreover, deleting the alpha7nAChR subunit protected the brain from loss of the synaptic markers synaptophysin and MAP2, reduced the gliosis, and preserved the capacity to elicit long-term potentiation otherwise deficient in APP mice. These results are consistent with the hypothesis that the alpha7nAChR plays a role in AD and suggest that interrupting alpha7nAChR function could be beneficial in the treatment of AD.
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PMID:Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. 1958 88

Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.
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PMID:Tau in Alzheimer disease and related tauopathies. 2067 74

The aggregation of PrP (Sc) is thought to be crucial for the neuropathology of prion diseases. A growing body of evidence demonstrates that the perturbation of the microtubule network contributes to PrP (Sc) -mediated neurodegeneration. Microtubules are a component of the cytoskeleton and play a central role in organelle transport, axonal elongation and cellular architecture in neurons. The polymerization, stabilization, arrangement of microtubules can be modulated by interactions with a series of microtubule-associated proteins (MAPs). Recent studies have proposed the abnormal alterations of two major microtubule-associated proteins, tau and MAP2, in the brain tissues of naturally occurred and experimental human and animal prion diseases. Increased total tau protein and hyperphosphorylation of tau at multiple residues are observed at the terminal stage of prion disease. The abnormal aggregation of tau protein disturbs its binding ability to microtubules and affects the microtubule dynamic. Significantly downregulated MAP2 is detected in the brain tissues of scrapie-infected hamsters and PrP106-126 treated cells, which corresponds well with the remarkably low levels of tubulin. In conclusion, dysfunction of MAP2/tau family leads to disruption of microtubule structure and impairment of axonal transport, and eventually triggers apoptosis in neurons, which becomes an essential pathway for prion to induce the neuropathology.
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PMID:Dysfunction of microtubule-associated proteins of MAP2/tau family in Prion disease. 2287 72

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