Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alteration of certain neuropeptide levels is a dramatic and consistent finding in the brains of AD patients. Levels of SS, which is normally present in high concentrations in cerebral cortex /75/, are consistently decreased in the neocortex, hippocampus and CSF of AD patients. In addition, decreased levels of SS correlate regionally with the distribution of neurofibrillary tangles in AD /47/. Most available evidence suggests that the subset of SS-containing neurons which lack NADPH diaphorase may be relatively vulnerable to degeneration in AD. CRF is another neuropeptide with frequently observed changes in AD. Levels of CRF, which is normally present in low concentrations in cortical structures /75/, are decreased in the neocortex and hippocampus of AD patients. However, levels of CRF in the CSF of AD patients are not consistently reduced, but this is likely a reflection of the relatively low levels of CRF normally present in cerebral cortex. Studies of deep gray structures in AD brains reveal elevated levels of GAL in the nucleus basalis. The ability of GAL to inhibit cholinergic neurotransmission has generated considerable interest, since degeneration of cholinergic neurons in the basal forebrain consistently occurs in AD. In addition, the presence of NADPH diaphorase in GAL-containing neurons may underlie the relative resistance of these neurons to degeneration. From the aforementioned studies, it appears that the neurons which are relatively resistant to neurodegeneration in AD contain NADPH diaphorase. It is hypothesized that the presence of NADPH diaphorase protects these neurons from neurotoxicity mediated by glutamate or nitric oxide. Although one recent study /147/ has reported an elevation of the microtubule-associated protein tau in the CSF of AD patients (and this could become a useful antemortem diagnostic tool for AD), no similar CSF abnormality has been found for any of the neuropeptides. Thus, the measurement of CSF neuropeptide levels presently remains unhelpful in the diagnosis and treatment of AD. Future research on neuropeptides and their potential roles in the pathogenesis, diagnosis, and treatment of AD will likely involve further development of pharmacological modulators of neuropeptide systems, together with the further study of brain neuropeptidases.
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PMID:Neuropeptide changes in cortical and deep gray structures in Alzheimer's disease. 884 72

Nitric oxide (NO.) can induce transient [Ca2+] changes in endothelial cells not different from receptor mediated signalling. Whether this Ca2+ signal may provide a link with IL-8 secretion induced by NO. donors was investigated in human endothelial cells. Sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose dependently increased IL-8 production in this cell type. Additive IL-8 secretion was found with TNFalpha. Buffering intracellular Ca2+ with MAPT/AM suppressed NO. induced [Ca2+]i changes and reduced subsequent IL-8 secretion. The additive effect of both NO. donors on TNFalpha induced IL-8 secretion was completely blocked in the presence of MAPT/AM. SKF 96365, which has been shown to block receptor mediated Ca2+ entry, and TMB-8, which blocks intracellular Ca2+ release, both inhibited IL-8 secretion, particularly when TNFalpha was used as a costimulator, indicating that [Ca2+]i changes are important components of IL-8 induction by NO..
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PMID:Intracellular Ca2+ dependence of nitric oxide mediated enhancement of interleukin-8 secretion in human endothelial cells. 935 Sep 89

Nitric oxide is a multifunctional molecule that acts as messenger/modulator in synaptogenesis and potential neurotoxin and is synthesized by three isozymes of Nitric oxide synthase (NOS). The role of NOS in Alzheimer's disease (AD) is unclear. For example, neurons in the entorhinal cortex (EC) that are highly vulnerable to neurodegeneration in AD express low levels of NOS and while it has been suggested that the inducible form of NOS is upregulated in AD, it is still not clear if the constitutive expressed isozyme (nNOS) is involved in the process of neurodegeneration. In order to better understand the role of nNOS in the pathogenesis of AD, sections from the EC and hippocampus (HC) of AD and control cases were immunohistochemically analyzed by single- and double-immunolabeling using antibodies against nNOS and PHF-tau. Semiquantitative assessment of numbers of nNOS expressing neurons in different areas of the HC and EC showed a remarkable loss of nNOS expressing neurons in the entorhinal cortex layer II and--less severe--CA1 and CA3 of the hippocampus in patients with AD. In addition, double-immunolabeling studies revealed that nNOS is strongly associated with neurofibrillary tangles and plaques. These findings indicate that nNOS expressing neurons are highly susceptible to neurodegeneration and that nNOS might contribute to the pathogenesis of AD.
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PMID:nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer's disease. 951 29

The recent re-discovery of axonal damage in multiple sclerosis has led to a renewed interest in neurodegenerative mechanisms of the disease. Transected or injured axons release several molecules from their proximal extremity into the intercellular space. Although these molecules can be measured, however, a biological marker of axonal and neuronal degeneration is still lacking. Cytoskeleton structural proteins like actin, tubulin, L-neurofilaments and tau protein, axon-specific antibodies, other neuronal or glial proteins like S-100, 14-3-3 and glial fibrillary acid protein, neuronal specific enolase, and nitric oxide and its metabolites are some of the putative markers that deserve further investigation and validation. At present, none of them fulfils the criteria of applicability in clinical practice, and the levels of N-acetylaspartate determined by magnetic resonance spectroscopy remain the most reliable measure of axonal damage.
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PMID:Biological indicators of the neurodegenerative phase of multiple sclerosis. 1465 89

Tyrosine nitration of proteins is emerging as a post-translational modification playing a role in physiological conditions. Looking for the molecular events triggered by nitric oxide in nerve growth factor-induced neuronal differentiation, we now find that nitration occurs on the microtubule-associated protein tau. In differentiated PC12 cells, we have identified as tau a nitrated protein that co-immunoprecipitates with alpha-tubulin and indicated that the modified protein is associated with the cytoskeleton but it is confined to a restricted cell region. This paper supplies the first evidence that nitration of tau occurs in a physiological process and suggests that it could play a role in neuronal differentiation.
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PMID:The nitration of tau protein in neurone-like PC12 cells. 1504 98

Production of nitric oxide (NO) by glial cells has been proposed to mediate cytotoxic effects on neighboring neurons. Although extensive genetic data implicate the beta amyloid peptide (Abeta) in the neurodegenerative cascade of Alzheimer's disease (AD), the molecular mechanisms underlying its effects on neurons and glia and the relationship between glial activation and neuronal death are not well understood. In AD, Abeta is sufficient to induce glial activation and promote the generation of inflammatory mediators including NO. We examined whether Abeta stimulated astrocytes to express nitric oxide synthase and produce NO. Also, we investigated whether astrocytic NO contributes to degenerative changes occurring in co-cocultured hippocampal neurons. We found that the treatment of rat hippocampal astrocyte cultures with Abeta(25-35) fragment up-regulated the mRNA and protein levels of both the inducible and neuronal forms of nitric oxide synthase (iNOS and nNOS, respectively) and increased the production of nitric oxide. Remarkably, hippocampal neurons co-cultured with astrocytes, previously stimulated with Abeta, displayed hyperphosphorylation of the microtubule-associated protein tau. This effect was attenuated by iNOS inhibitors, suggesting the role of overproduction of NO by reactive astrocytes in AD pathogenesis.
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PMID:Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons. 1534 Nov 83

Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder. AD patients are affected by cognitive and memory deterioration. Cerebral degeneration, with selective neuronal death induced by extracellular amyloid deposits in the form of senile plaques and intracellular neurofibrillary tangles composed of helical paired tau protein, is the best-studied pathological event related to AD. Presenilins and apolipoprotein E are other neurotoxic agents involved in the pathogenesis of AD. A large body evidence has shown that permanent activation of glial cells in the brains of AD patients promotes the production of excessive quantities of free radicals, nitric oxide, and cytokines which could be detrimental to neuronal cells. Damage to the blood-brain barrier by inflammatory processes result in the influx of peripheral immune system cells and local immune reactions. Inhibition of ROS and NO overproduction as well as endogenic regulation of cytokine induction could be of therapeutic importance and delay neurodegeneration in AD.
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PMID:[Alzheimer's disease as neurodegenerative disorder]. 1664 90

Among the wide range of neuro-inflammatory signalling molecules released by beta-amyloid-stimulated astroglial cells, nitric oxide (NO) plays a fundamental role in AD aethiopathogenesis since it directly promotes neuronal tau protein hyperphosphorylation leading to neurofibrillary tangle formation. Synthetic cannabinoids (CBs), via a selective CB1 receptor activation, negatively modulates both iNOS protein expression and NO production induced by pro-inflammatory stimuli. In this study we investigated the role of both the non-selective WIN 55,212-2 and the selective CB1 receptor agonist, ACEA, on: (i) NO production, (ii) iNOS protein expression in (1-42) beta-amyloid peptide (Abeta)-stimulated C6 rat glioma cells and (iii) tau protein hyperphosphorylation in co-cultured differentiated PC12 neurons. Our results demonstrated that synthetic CBs, by a selective CB1 effect, down-regulate iNOS protein expression and NO production in Abeta-stimulated C6 cells. This effect leads, in turn, to a significant and concentration-dependent inhibition of NO-dependent tau protein hyperphosphorylation in co-cultured PC12 neurons. The results of the present study extend our knowledge about the neuroprotective actions of synthetic CBs on Abeta-dependent neurotoxicity in vitro. Furthermore, our study allows us to identify, in the CB1-mediated inhibition of astroglial-derived NO, a new potential target to blunt tau hyperphosphorylation and the consequent related tauopathy in AD.
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PMID:CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons. 1683 32

Nitric oxide [NO] is known to have vasoregulatory, neuroprotective and blood-brain barrier (BBB) related transport functions in the human CNS. Altered NO levels are suspected of contributing to neurodegenerative disorders, including Alzheimer's disease (AD). NO is produced as a result of the activity of one or more of three isoforms of nitrogen oxide synthase (NOS). In this study we compared Alzheimer and normative comparison brain samples, from temporal and calcarine cortices, with respect to the interactive correlation between eNOS, iNOS and nNOS isoform positive capillaries and the presence of neurofibrillary tangles (NFTs) and senile plaques (SPs). Cortical samples were taken from the superior temporal and calcarine cortices of 10 confirmed AD and 10 non-demented comparison group (CG) brains. Contiguous coronal sections were stained using immunohistochemistry techniques to stain for tau protein, beta amyloid (A beta) n-termini ([40 and 42]), eNOS, iNOS and nNOS. The densities of NFTs, SPs, and eNOS, iNOS and nNOS positive capillaries were recorded. Non-parametric statistical analyses were applied to the data. Our results demonstrate a significant negative correlation between the presence of eNOS positive capillaries and NFTs and SPs in both cortices in AD brains. Our results support the view that eNOS activity should be targeted for further investigation, and that factors involved in the regulation of NO production may be amenable to therapeutic intervention.
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PMID:Significant negative correlations between capillary expressed eNOS and Alzheimer lesion burden. 1966 May 23

Alzheimer disease (AD) is the most common neurodegenerative disease, but there is currently no effective treatment available because the etiology or mechanism of AD is still unclear. Many neurodegenerative diseases feature inclusions, which contain accumulations of misfolded, aggregated proteins. Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological hallmarks of AD. NFTs are composed of tubular filaments, and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature is excessive generation of nitric oxide synthetase, reactive nitrogen species, and reactive oxygen species. Protein disulfide isomerase (PDI) is a member of the thioredoxin (TX) superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum (ER). Nitric oxide (NO)-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response in neurodegenerative diseases. In this study, we found NFTs positive for anti-PDI-antibody in the brain of patients with AD. As far as we know, this is the first report of anti-PDI-antibody-immunopositive inclusions in AD. In AD, NO may inhibit PDI by inducing S-nitrosylation, which inhibits its enzymatic activity and thus allows protein misfolding to occur. Consequently, the accumulation of misfolded proteins induces ER stress. The ER stress can cause apoptosis of neuronal cells. These results suggest that PDI could be a therapeutic target to prevent ER stress in neuronal cells in AD.
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PMID:Protein disulfide isomerase-immunopositive inclusions in patients with Alzheimer disease. 2055 Sep 46


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