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)

The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.
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PMID:Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. 777 9

Alzheimer's disease is histopathologically characterized by neurofibrillary tangles, formed by the abnormally high phosphorylated tau protein, and senile plaques which largely consist of the beta/A4-amyloid peptide. Metabolism of the amyloid precursor protein and its processing into beta/A4-amyloid is regulated by protein phosphorylation. Thus, an imbalance between protein phosphorylation and dephosphorylation might be crucial for the development of the molecular hallmarks of Alzheimer's disease. We report here that chronic infusion into rat brain ventricles of okadaic acid, a specific inhibitor of the serine/threonine protein phosphatases 1 and 2A, results in a severe memory impairment, accompanied by a paired helical filament-like phosphorylation of tau protein and the formation of beta/A4-amyloid containing plaque-like structures in gray and white matter areas.
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PMID:Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. 859 39

In view of existing drugs (acetylcholine esterase inhibitors) and emerging therapeutic compounds (e.g. neuroprotective and anti-inflammatory compounds), CSF markers would be of great use to improve the clinical diagnostic accuracy of Alzheimer's disease (AD). Correct identification of AD would be especially important early in the course of the disease, when the clinical diagnosis is difficult, and drugs have the greatest potential of being effective. Biochemical markers for AD include ApoE genotyping, where the ApoE epsilon 4 allele has proven to have a high predictive value for AD. Biochemical markers for AD also include several potential cerebrospinal fluid (CSF) markers: beta-amyloid(1-42), possibly reflecting amyloid deposition and formation of senile plaques; PHFtau protein a marker for the phosphorylation state of tau, and formation of neurofibrillary tangles; (total)tau protein, a normal axonal protein, as a marker for ongoing neuronal and axonal degeneration; synaptic vesicle proteins, e.g. synaptotagmin, a synaptic vesicle protein which is found in the CSF, as markers for synaptic activity or degeneration; neuromodulin or growth-associated protein GAP-43, as a marker for synaptic degeneration, and the CSF/serum albumin ratio, as a marker for blood-brain barrier damage, used to exclude patients with concomitant cerebrovascular pathology. However, although CSF markers may identify different pathogenic processes in AD, there is no such process that is specific for AD, and thus little hope of ever finding a single CSF biochemical marker that gives an absolute discrimination between AD and other dementia disorders. Instead, combination of several CSF biochemical markers, each reflecting a pathogenic process, may increase both the sensitivity and specificity. Further, the accuracy of the clinical diagnosis of AD may increase if the diagnosis is based on the summarised information gained from the clinical examination, brain-imaging techniques (SPECT, CT/MRT scans), and biochemical markers. Using this approach, CSF markers have a large potential to help to differentiate AD from the most problematic differential diagnoses, especially age-associated memory impairment, depressive pseudo-dementia, Parkinson's disease, and frontal lobe dementia.
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PMID:Combination of the different biological markers for increasing specificity of in vivo Alzheimer's testing. 970 Jun 60

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

Alzheimer's disease (AD) is characterized by memory impairment leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid beta peptide, A beta, whereas NFTs contain hyperphosphorylated forms of the microtubule-associated protein tau (tau). Familial AD (FAD) mutations either elevate A beta synthesis by favoring 'secretase' of the Alzheimer beta-amyloid precursor protein (APP) or enhance the fibrillogenic properties of this peptide. Mutations in the tau gene cause a different disease denoted FTPD-17, but suggest that the aberrant forms of tau seen in AD are unlikely to be benign. These findings imply a complex pathogenic cascade in AD and important goals of transgenic modeling are to capture and stratify this pathogenic process. Several laboratories have created APP transgenic (Tg) mice that exhibit AD-like amyloid pathology and A beta burdens. These Tg lines also exhibit deficits in spatial reference and/or working memory, with immunization against A beta attenuating both AD-associated phenotypes. Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type (wt) tau isoforms present in AD have proven more elusive. Creation of animal models with robust amyloid and tau pathologies, yet free of irrelevant confounding pathologies, remains a major objective in this field.
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PMID:Mouse models of Alzheimer's disease: the long and filamentous road. 1450 12

Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
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PMID:Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. 1471 90

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.
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PMID:The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. 1517 40

We have found recently that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rats and the potential underlying mechanisms by using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase, and a key enzyme in melatonin biosynthesis. We have found that injection of haloperidol into the lateral ventricle and into peritoneal cavity compromises spatial memory retention of rats and induces hyperphosphorylation of microtubule-associated protein tau at tau-1 (Ser199/Ser202) and PHF-1 (Ser396/Ser404) epitopes. At mean time, the activity of protein phosphatase-2A (PP-2A), a deficit phosphatase in the Alzheimer's disease brain and superoxide dismutase decreases with an elevated level of malondialdehyde. Supplementation with melatonin by prior injection for 1 wk and reinforcement during the haloperidol administration significantly improves memory retention deficits, arrests tau hyperphosphorylation and oxidative stress, and restores PP-2A activity. These results strongly support the involvement of decreased melatonin in Alzheimer-like spatial memory impairment and tau hyperphosphorylation, and PP-2A may play a role in mediating aberrant melatonin-induced lesions.
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PMID:Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat. 1529 64

The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment.
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PMID:Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat. 1562 Jul 22

Alois Alzheimer couldn't have chosen a name more appropriate than neurofibrillary tangles when one hundred years ago (Alzheimer, 1906) he presented this histopathological hallmark of the progressive dementing disorder, which got named after him as Alzheimer disease. Both, the structure and as well as the molecular composition of neurofibrillary tangles have baffled neuroscientists for many years. It was not till 1963 when with the help of the electron microscope the tangles were found to be made up of paired helical filaments (PHF). It took another 23 years before microtubule associated protein tau was immunohistochemically identified as the part of neurofibrillary tangles (Grundke-lqbal, 1986 a). The same year it was shown that tau protein in Alzheimer disease brain was abnormally hyperphosphorylated (Grundke-Iqbal, 1986 b). In 1988 Michal Novak, Cesar Milstein and Claude Wischik produced monoclonal antibody that was able to recognize then unknown protein in PHF. The antibody (MN423) allowed its isolation and let to full molecular characterization as protein tau. These studies provided molecular proof that tau protein was the major and an integral component of the PHF (Wischik et al, 1988 a, b, Goedert et al, 1988, Novak et al, 1989, 1991). Over the years the significance of tau pathology for the neurodegenerative diseases was discussed and often questioned. However, detailed studies of the maturation and distribution of NFTs, showing correlation with degree of cognitive decline and memory impairment in Alzheimer's disease (Braak and Braak, 1991), together with discovery of tau gene mutations causing fronto-temporal dementia in many families (Hutton et al, 1998) promoted tau as the major pathogenic force in neurodegenerative cascade. Further studies focused on tau dysfunctions revealed truncation and phosphorylation as two major posttranslational modifications responsible for toxic gain of function as an underlying cause of tauopathies including Alzheimer's disease (Alonso et al, 1996, Novak et al, 1989, 1991, 1993, Avila et al, 2006). Recently, in vivo experiments using transgenic expression of conformationally modified truncated tau showed that truncation is able to drive neurofibrillary pathology ofAlzheimer's type (Zilka et al, 2006). Finally, after one hundred years the exact nature of the neurofibrillary tangles and their role in neurodegeneration is beginning to be unraveled.
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PMID:From tangles to tau protein. 1726 84


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