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)

Alzheimer's disease is a degenerative disorder of the human central nervous system that results in a progressive loss of memory and intellectual abilities. It is strongly related to aging and it is thus assumed that 0.5% of the total population, and up to 30% of eighty-year-olds suffer from the disease. Many require expensive institutional care, often over long periods, as there is no effective treatment at present. Abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathological lesions that characterize the brains of patients with Alzheimer's disease. The amyloid plaque consists mainly of a soluble polypeptide of 42-43 amino acids called beta-amyloid. beta-Amyloids is derived by an alternative cleavage of the much larger amyloid precursor protein (APP), but it is not known which proteolytic enzyme is responsible for this alternative cleavage. In contrast to plaques, the neurofibrillary tangles are formed intracellularly and the number of them seems to correlate with the progression of the disease. Their main components are paired helical filaments (PHF) which seem to consist almost entirely of the protein tau. The normal function of tau is to bind to microtubules and thereby stabilize the nerve cell's structure and integrity. In contrast to normal tau, PHF-tau is heavily phosphorylated, and it is assumed that this phosphorylation is the underlying cause of the formation of PHF and the neurofibrillary tangles. Despite extensive research it is still not known which enzymes are responsible for the over phosphorylation of tau that occurs in Alzheimer's disease. If they could be identified and controlled pharmacologically, an effective treatment of the disease might be possible.
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PMID:[Tau, amyloid and Alzheimer's disease]. 811 89

Alzheimer's disease (AD) is characterized pathologically by two distinguishable deposits in the brain, namely senile plaques and neurofibrillary tangles (NFT). Senile plaques are composed of fragments of the amyloid precursor protein, whereas NFT are composed primarily of paired-helical filaments (PHF). The latter are in turn composed principally of the microtubule-associated protein, tau. Tau in PHF is highly and unusually phosphorylated but the mechanisms leading to this unusual phosphorylation are not known. Using a combination of immunoblotting and kinase assays, we demonstrate that a discreet set of kinases copurify with PHF. One of these kinases was found by immunoblotting to be alpha-calcium-calmodulin-dependent kinase II (alpha-CaM kinase). Immunogold labeling revealed that alpha-CaM kinase was localized to a novel globular membranelike structure found at the ends of PHF. Since previous studies have shown alpha-CaM kinase to be involved in memory, its association with PHF may have important implications in understanding memory loss in AD. We also discuss the possibility that the association of alpha-CaM kinase with PHF may indicate sites where tau protein is converted into PHF.
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PMID:alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer's disease. 880 91

Both the early and late-onset Alzheimer's disease affect millions of people throughout the world. A number of molecules have been implicated in the pathogenesis of Alzheimer's disease. These include presenilin 1 and 2 (PS1 and PS2), a beta-amyloid peptide, and tau protein. Presenilin 1 and 2 genes implicated in the early-onset familial Alzheimer's disease have been cloned. Both PS1 and PS2 are integral membrane proteins and may function as receptors or channel proteins. Missense mutations in PS1 and PS2 genes have been found in families that cosegregate with early-onset Alzheimer's disease. Overexpression of the mutated PS1 gene produced amyloid plaques in the brain of transgenic mice. Secreted beta-amyloid protein similar to that in the senile plaques of Alzheimer's disease was found to be elevated in fibroblast media from subjects with PS1 or PS2 mutations. Transgenic mice which carried the mutant form of the beta-amyloid precursor protein gene expressed high concentrations of mutant copy of the gene and exhibited abundant amyloid plaques in the brain and memory loss. The mutated PS2 gene enhanced apoptotic activity. This enhanced apoptotic activity may accelerate the process of neurodegeneration leading to an earlier age in the onset of the disease. Identification of lesions in the molecules that are important in the Alzheimer's disease should allow developing therapeutic approaches for its treatment.
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PMID:Genes implicated in the pathogenesis of Alzheimer's disease. 920 74

The diagnosis, genetics, risk factors, neuropathology, and pathogenesis of Alzheimer's disease (AD) are discussed. AD is a degenerative brain disorder and is the leading cause of dementia. Clinical manifestations of AD are primarily the progressive loss of memory and language. Other signs and symptoms of the disease include psychiatric and behavioral disturbances and impairments in the performance of activities of daily living (ADL). To diagnose AD, other causes of dementia-- some of which may be reversible--must be ruled out by laboratory testing and neuroimaging. The pathogenic process that causes AD has not been fully delineated; however, it clearly leads to neuropathology characterized by neuritic plaques, neurofibrillary tangles, and loss of cholinergic neurons in the nucleus basalis of Meynert. Genetic factors, including mutations in the amyloid precursor protein and the two presenilin genes, appear important in the development of early-onset familial AD, whereas the apolipoprotein E genotype influences the timing of disease onset after age 65. Genetic factors may promote or accelerate deposition of beta-amyloid protein to form plaques, as well as abnormal phosphorylation of tau protein to form neurofibrillary tangles. Several biochemical factors, such as inflammation, oxidative stress, and hormonal deficiency (estrogen), and other unmodifiable risk factors, notably aging, also play a role in the pathogenic process. The loss of neurons and synaptic connections is selective and causes deficiencies in cholinergic and other neurotransmitter systems, leading to cognitive dysfunction, psychiatric and behavioral disturbances, and eventual loss of ability to perform ADL. The etiology and pathogenesis of AD are highly complex; more effective therapeutic approaches than those currently available will be needed to address these underlying factors more specifically.
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PMID:Etiology and pathogenesis of Alzheimer's disease. 980 5

Cerebrospinal fluid (CSF) tau protein phosphorylated at both Thr231 and Ser235 sites (CSF/phospho-tau(231-235)) and total tau (CSF/total-tau) were quantified by sandwich ELISA in 20 patients with mild cognitive impairment (MCI) who eventually developed AD on follow-up as well as seven memory complainers with no objective memory loss. 13/20 (65%) of the MCI patients had high CSF/total-tau and detectable levels of CSF/phospho-tau(231-235), whereas these markers were low and under a detectable level in all of the memory complainers. Although either a total-tau, phospho-tau measurement or a combination of these can help in predicting if MCI will develop AD, our results suggest that the pathogenic steps of AD may be at the stage that finally leads to an accumulation of abnormally phosphorylated tau and neuron death, at least in some brain areas, when MCI patients present with the earliest detectable clinical symptoms of dementia.
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PMID:CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. 1103 Oct 97

Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. Here we describe a K257T missense mutation in exon 9 of Tau. The proband, a 47-yr-old male, presented with severe personality changes followed by semantic memory loss. A diagnosis of Pick's disease was made. The symptoms progressed until death at age 51. The proband's brain showed a marked frontotemporal atrophy that was most pronounced in the temporal lobes. Numerous tau-immunoreactive Pick bodies were present in the neocortex and the hippocampal formation, as well as in some subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. Diffuse staining for hyperphosphorylated tau was also observed in some nerve cell bodies. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa and 2 very minor bands of 68 and 72 kDa. Upon dephosphorylation, these bands resolved into 6 bands consisting of 3-repeat and 4-repeat tau isoforms, with an overall preponderance of 3-repeat tau. Isolated tau filaments were narrow, irregularly twisted ribbons. Biochemically, recombinant tau proteins with the K257T mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. In addition, the K257T mutation was found to stimulate heparin-induced assembly of 3-repeat tau into filaments. Taken together, the present findings indicate that the K257T mutation in Tau can cause a dementing condition similar to Pick's disease.
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PMID:Tau gene mutation K257T causes a tauopathy similar to Pick's disease. 1108 77

Recently, it has become important to diagnose Alzheimer's Disease (AD) at an early stage due to the development of AD therapy. Also, there is increasing recognition of a class of elderly people with complaints of memory loss but who nevertheless do not meet the criteria for dementia. "Mild cognitive impairment" (MCI) is the term used for this disorder, and amnestic MCI is highly converted to AD. In this study we evaluated the accuracy of diagnosis of amnestic MCI by cerebrospinal fluid total-tau protein (CSF/total-tau), cerebrospinal fluid amyloid beta 1-42 protein (CSF/A beta 1-42), and cerebral blood flow in the posterior cingulate cortex using SPECT. CSF/total-tau was the most appropriate to discriminate between normal cognitive individuals and those with amnestic MCI. We also evaluated the CSF/total-tau and MRI images between patients with stable MCI and those with progressive MCI, including those who converted to AD in the following two years. The stable type was characterized by normal CSF/total-tau levels and relatively high grade periventricular white matter lesions (PWML). Conversely, the progressive type was characterized by high CSF-tau levels and relatively low grade PWML. We speculate that stable MCI is due to ischemic change with in the white matter lesion, while progressive MCI may represent a previous stage of AD.
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PMID:[Diagnosing the mild cognitive impairment stage of Alzheimer's disease]. 1516 76

Alzheimer's disease is an age-related neurodegenerative disorder that is characterized by a progressive loss of memory and deterioration of higher cognitive functions. The brain of an individual with Alzheimer's disease exhibits extracellular plaques of aggregated beta-amyloid protein (Abeta), intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Abeta accumulation may trigger or contribute to the process of neurodegeneration. However, the mechanisms whereby Abeta induces basal forebrain cholinergic cell loss and cognitive impairment remain obscure. Physiologically relevant concentrations of Abeta-related peptides have acute, negative effects on multiple aspects of acetylcholine (ACh) synthesis and release, without inducing toxicity. These data suggest a neuromodulatory influence of the peptides on central cholinergic functions. Long-term exposure to micromolar Abeta induces cholinergic cell toxicity, possibly via hyperphosphorylation of tau protein. Conversely, activation of selected cholinergic receptors has been shown to alter the processing of the amyloid precursor protein as well as phosphorylation of tau protein. A direct interaction between Abeta and nicotinic ACh receptors has also been demonstrated. This review addresses the role of Abeta-related peptides in regulating the function and survival of central cholinergic neurons and the relevance of these effects to cholinergic deficits in Alzheimer's disease. Understanding the functional interrelations between Abeta peptides, cholinergic neurons and tau phosphorylation will unravel the biologic events that precede neurodegeneration and may lead to the development of more effective pharmacotherapies for Alzheimer's disease.
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PMID:Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. 1564 84

Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.
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PMID:Role of melatonin in Alzheimer-like neurodegeneration. 1636 9

Alzheimer's disease, an age-related neurodegenerative disorder, is characterized clinically by a progressive loss of memory and cognitive functions. Neuropathologically, Alzheimer's disease is defined by the accumulation of extracellular amyloid protein deposited senile plaques and intracellular neurofibrillary tangles made of abnormal and hyperphosphorylated tau protein, regionalized neuronal death, and loss of synaptic connections within selective brain regions. Evidence has suggested a critical role for amyloid-beta peptide metabolism and oxidative stress in Alzheimer's disease pathogenesis and progression. Among the other indices of oxidative stress in Alzheimer's disease brain are protein carbonyls and 3-nitrotyrosine, which are the markers of protein oxidation. Thus, in this review, we discuss the application of redox proteomics for the identification of oxidatively modified proteins in Alzheimer's disease brain and also discuss the functions associated with the identified oxidized proteins in relation to Alzheimer's disease pathology. The information obtained from proteomics may be helpful in understanding the molecular mechanisms involved in the development and progression of Alzheimer's disease as well as of other neurodegenerative disorders. Further, redox proteomics may provide potential targets for drug therapy in Alzheimer's disease.
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PMID:Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics. 1686 Jul 90


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