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

Establishing the diagnosis in patients with clinical signs and symptoms suggesting primary degenerative disease with marked frontal lobe involvement is difficult. Neuroimaging methods, in particular positron emission tomography (PET) with the tracer 18fluoro-2-deoxyglucose (FDG) and cerebrospinal fluid (CSF) examination of beta-amyloid and tau-protein levels may give additional information. We report five patients with clinical and radiological features of degenerative dementia with predominantly frontal involvement and one patient with primary progressive aphasia Diagnostic work-up included computed tomography (CT), magnetic resonance imaging (MRI), PET and tau-protein and beta-amyloid level determination in CSF. While neuropsychological performance varied among patients, CT and MRI demonstrated persistently frontal lobe involvement. PET revealed corresponding changes with frontal hypometabolism, but in addition, four patients (among them two with no corresponding temporal changes in CT or MRI) showed a decreased glucose uptake in the temporal cortices. CSF samples from five patients revealed elevated beta-amyloid 1-42 and tau levels in three and two patients, respectively. Reduced beta-amyloid 1-40 was found in two patients. We conclude that occurrence of clinical symptoms of frontotemporal dementia is accompanied by frontal hypometabolism regardless of additional clinical findings. The value of determination of beta-amyloid and tau protein levels remains to be determined.
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PMID:Frontotemporal dementia: clinical, neuroimaging, and molecular biological findings in 6 patients. 1182 9

Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.
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PMID:The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. 1195 56

In vivo, post-mortem and biopsy data suggest that coupled declines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.
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PMID:Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease. 1471 41

Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.
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PMID:Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease. 1501 15

Alzheimer's disease (AD) is characterized by the abnormal extracellular accumulation of amyloid beta-peptide (Abeta) into neuritic plaques and the intraneuronal aggregation of the microtubule-associated protein tau to form neurofibrillary tangles. These molecular events are implicated in the selective damage to neural systems critical for the brain functions that are impaired in AD. Impairment of cholinergic neurotransmission may be an important factor underlying the defects in cognition and memory that characterize AD. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, cause symptomatic improvement by inhibiting the breakdown of the neurotransmitter acetylcholine to increase its synaptic availability and, in the case of galantamine, by also allosterically potentiating nicotinic cholinergic receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and statins, have shown some benefit in epidemiological studies and clinical trials although compelling evidence of their efficacy is lacking. Memantine, shown to cause cognitive and functional improvement, is not an ChE inhibitor and does not interact with marketed ChE inhibitors. While the mechanism of action of memantine in AD is not known, the principal pharmacologic actions at therapeutic dose are inhibition of ionotropic neurotransmitter receptors, specifically N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA antagonists, memantine causes behavioral activation associated with enhanced cerebral glucose utilization. Studies have shown that memantine can reverse the decreased metabolic activity associated with AD, possibly accounting for its beneficial effects on cognition and global functioning. Memantine also has neuroprotective properties and can inhibit Abeta-induced neurodegeneration.
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PMID:What is the rationale for new treatment strategies in Alzheimer's disease? 1524 Dec 94

Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide beta-N-acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake/metabolism in AD and other tauopathies.
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PMID:O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. 1524 77

The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.
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PMID:MRI and CSF studies in the early diagnosis of Alzheimer's disease. 1532 64

Alzheimer's disease is defined in part by the intraneuronal aggregation of tau protein into filamentous lesions. The pathway is accompanied by posttranslational modifications including phosphorylation and glycation, each of which has been shown to promote tau fibrillization in vitro when present at high stoichiometry. To clarify the site-specific impact of posttranslational modification on tau fibrillization, the ability of recombinant full-length four repeat tau protein (htau40) and 11 pseudophosphorylation mutants to fibrillize in the presence of anionic inducer was assayed in vitro using transmission electron microscopy and laser light scattering assays. Tau glycated with d-glucose was examined as well. Both glycated tau and pseudophosphorylation mutants S199E, T212E, S214E, double mutant T212E/S214E, and triple mutant S199E/S202E/T205E yielded increased filament mass at equilibrium relative to wild-type tau. Increases in filament mass correlated strongly with decreases in critical concentration, indicating that both pseudophosphorylation and glycation promoted fibrillization by shifting equilibrium toward the fibrillized state. Analysis of reaction time courses further revealed that increases in filament mass were not associated with reduced lag times, indicating that these posttranslational modifications did not promote filament nucleation. The results suggest that site-specific posttranslational modifications can stabilize filaments once they nucleate, and thereby support their accumulation at low intracellular tau concentrations.
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PMID:Pseudophosphorylation and glycation of tau protein enhance but do not trigger fibrillization in vitro. 1536 24

The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated, and no studies have been conducted in this area using a gene profiling approach. We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin-like growth factor I (IGF-1) or basic fibroblast growth factor (bFGF), to identify differentially regulated genes that may function in growth factor signaling, response to oxygen-glucose deprivation (OGD), and most importantly, cell survival. Primary rat cortical cultures were treated with bFGF or IGF-1 for 2, 24, or 24 h followed by OGD for 90 min, and compared with cells that were subject to OGD without growth factor pretreatment. Although the majority of surveyed genes were unchanged in all experimental treatments, 175 genes (10% of the cDNAs on the chip) were found to be differentially regulated in at least one of the treatment conditions. Hierarchical clustering of these 175 genes was used to identify four expression clusters: IGF-1 regulated, bFGF regulated, OGD regulated, and putative neuroprotective genes. Further analysis using realtime RT-PCR confirmed that we had identified genes that are regulated by single growth factors, as well as several more that are co-regulated by both IGF-1 and bFGF. These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction (CD44, DTR, DUSP6, EPS8, IGFBP3), DNA repair and transcription (FOXJ1), metabolic homeostasis (RASA1, SHMT2), cytoskeletal stability (MSN, MAPT) and cholesterol biosynthesis (FDFT1, FDPS).
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PMID:Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with IGF-1 or bFGF. 1553 Jun 50

The effects of a single intraperitoneal injection of a non-metabolizable glucose analog 2-deoxyglucose (2-DG, 500 mg/kg) on the levels of beta-APP expression, and phosphorylated and unphosphorylated tau protein in the rat cerebral cortex were investigated. The effects of 2-DG on the ultrastructure of cortical neurons with particular emphasis on the morphology of the Golgi apparatus, and on brain bioenergetics assessed by in vivo 31P-MRS technique were also evaluated. Seven and a half hours after injection of 2-deoxyglucose a significant increase in brain cortex beta-APP expression, increased tau phosphorylation, and a marked relative expansion of the trans- part of the Golgi intracellular secretory pathway in cortical neurons has been found. The changes of beta-APP expression and tau phosphorylation appeared within 1 h after 2-DG application and continued for at least 24 h. However, brain 31P resonance spectra remained unchanged for up to 7.5 h after 2-DG. It is suggested that the increase of beta-APP expression represents a response of brain tissues to 2-DG-evoked biochemical stress, while tau hyperphosphorylation and the change in Golgi morphology may be secondary phenomena.
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PMID:2-deoxyglucose induces beta-APP overexpression, tau hyperphosphorylation and expansion of the trans-part of the Golgi complex in rat cerebral cortex. 1558 66


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