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 local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.
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PMID:Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. 1047 76

Alzheimer's disease (AD) is characterized by neuropil threads composed of structurally abnormal neurites, neurons containing paired helical filaments of tau protein, and extracellular deposits of amyloid-beta (Abeta) peptide, a protein fragment having neurotoxic and glial immune response activating potential. In the present study, we demonstrate that an acute intracerebroventricular (icv) injection of Abeta(1-42) in the mouse induces a time- and dose-dependent production of IL-1alpha, IL-1beta, IL-6 and MCP-1 in the hippocampus and cortex as measured by ELISA. Cytokine and chemokine levels were maximal at 9 h, with MCP-1 and IL-1alpha remaining elevated over a 24 h period and IL-1beta remaining elevated over a 48 h period. The temporal profile of Abeta-induced cytokine induction differed from that observed for LPS. Following an icv injection of LPS, maximal levels of IL-1alpha, IL-1beta, IL-6 and MCP-1 were attained by 9 h and, except for MCP-1, returned to levels indistinguishable from control at 24 h. MCP-1 remained elevated at 24 h and returned to basal levels at 48 h. In contrast, little production of TNF-alpha was observed under either Abeta or LPS acute stimulus conditions. Treatment with anti-inflammatory agents such as prednisolone, dexamethasone, or IL-10 inhibited both Abeta- and LPS-induced cytokine and chemokine production in the brain. In summary, icv administration of Abeta and LPS induced elevated brain levels of pro-inflammatory cytokines that could be inhibited by immune suppressing drugs and anti-inflammatory proteins, thus providing support for the utility of anti-inflammatory therapeutics in modulating the immunopathology observed in brain inflammatory diseases such as AD.
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PMID:IL-10 and glucocorticoids inhibit Abeta(1-42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system. 1271 28

Methamphetamine (METH) causes irreversible damage to brain cells leading to neurological and psychiatric abnormalities. However, the mechanisms underlying life-threatening effects of acute METH intoxication remain unclear. Indeed, most of the hypotheses focused on intra-neuronal events, such as dopamine oxidation, oxidative stress and excitotoxicity. Yet, recent reports suggested that glia may contribute to METH-induced neuropathology. In the present study, we investigated the hippocampal dysfunction induced by an acute high dose of METH (30 mg/kg; intraperitoneal injection), focusing on the inflammatory process and changes in several neuronal structural proteins. For that, 3-month-old male wild-type C57BL/6J mice were killed at different time-points post-METH. We observed that METH caused an inflammatory response characterized by astrocytic and microglia reactivity, and tumor necrosis factor (TNF) system alterations. Indeed, glial fibrillary acidic protein (GFAP) and CD11b immunoreactivity were upregulated, likewise TNF-alpha and TNF receptor 1 protein levels. Furthermore, the effect of METH on hippocampal neurons was also investigated, and we observed a downregulation in beta III tubulin expression. To clarify the possible neuronal dysfunction induced by METH, several neuronal proteins were analysed. Syntaxin-1, calbindin D28k and tau protein levels were downregulated, whereas synaptophysin was upregulated. We also evaluated whether an anti-inflammatory drug could prevent or diminish METH-induced neuroinflammation, and we concluded that indomethacin (10 mg/kg; i.p.) prevented METH-induced glia activation and both TNF system and beta III tubulin alterations. In conclusion, we demonstrated that METH triggers an inflammatory process and leads to neuronal dysfunction in the hippocampus, which can be prevented by an anti-inflammatory treatment.
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PMID:Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. 2007 21

Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer's disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFkappa-beta with the consequent release of cytokine mediators such as TNF-alpha, IL-6 and IL-1beta. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3beta, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species.
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PMID:Neuroimmunomodulation in the pathogenesis of Alzheimer's disease. 2013 3

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid-beta (Abeta) peptide in brain regions that are important for memory and cognition. The buildup of Abeta aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Abeta-induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 microm of Abeta(25-35) in the absence or in the presence of melatonin (25, 50, or 100 microm). In addition, the authors have investigated the involvement of GSK-3beta, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Abeta-induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Abeta(25-35). In addition, melatonin significantly reduced the activation of GSK-3beta, the phosphorylation of tau protein, the glial activation and the Abeta-induced increase of TNF-alpha and IL-6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Abeta-induced phosphorylation of tau protein, and preventing GSK-3beta activation and neuroinflammation.
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PMID:Amyloid-beta neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK-3beta, tau and neuroinflammation. 2013 1