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 the most common type of progressive and debilitating dementia affecting aged people. In some early--as well as late--onset familial cases, a genetic linkage with chromosomes 14, 21 (early-onset) or 19 (late-onset) has been indicated. Furthermore, a direct or indirect role has been attributed to normal or structurally altered amyloid beta-protein (concentrated in senile plaques) and/or excessively phosphorylated tau protein (located in neurofibrillary tangles). Degeneration of cholinergic neurons and concomitant impairment of cortical and hippocampal neurotransmission lead to cognitive and memory deficits. Several compounds are being tested in attempts to prevent and/or cure Alzheimer's disease, including tacrine, which has very modest efficacy in a sub-group of patients, and new acetylcholinesterase inhibitors. Pilot experiments have also been launched using nerve growth factor (NGF) to prevent or stabilize the processes of cholinergic pathway degeneration. Alternatively, antioxidants, free radical scavengers and/or non steroidal anti-inflammatory agents may be screened as potential therapies for neurodegenerative diseases induced by multiple endogenous and/or exogenous factors. The recent use of transgenic mice, in parallel with other genetic, biochemical and neurobiological systems, in vivo and/or in vitro (cell cultures), should accelerate the discovery and development of specific drugs for the treatment of Alzheimer's disease.
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PMID:Alzheimer's disease: fundamental and therapeutic aspects. 787 58

Information on the molecular biology of Alzheimer's disease (AD) pointing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropathologic examination at autopsy or biopsy; however, the accuracy of diagnosis based on standard neuropsychological testing and inclusion criteria has improved considerably. Senile plaques consist of a central core of amyloid fibrils surrounded by dystrophic axons. The main component of senile plaque amyloid is a 39-to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid precursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chromosome 21. Factors that may influence APP metabolism include activation of phospholipase C, phosphorylation, and the cholinergic system. The microtubule-associated protein tau may contribute to the neurofibrillary tangles of AD. In AD all six adult isoforms of tau can become maximally phosphorylated and can, rather than binding to microtubules, bind to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipoprotein E phenotype to familial late-onset AD. Acetylcholinesterase inhibitors appear to improve cognitive function but may be limited in utility by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve growth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal anti-inflammatory drugs, and estrogens. Research into the molecular biology of Alzheimer's disease has begun to point to possible causes of and treatments for this condition.
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PMID:Molecular basis of Alzheimer's disease. 880 75

A 53-year-old Japanese woman with a point mutation in mitochondrial DNA (tRNALeu(UUR), nt3243) consistent with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and Alzheimer-type brain pathology is reported. This woman had suffered myopathy and psychosis without any clinical evidence of, stroke-like episodes during the last 10 years of her life, and had died after an accident. At autopsy 30 h post mortem, a part of the brain was snap frozen for biochemical and histochemical studies, and the remaining part was processed for a routine examination and electron microscopy. In the brain there were no ischemic lesions. Instead, primitive/diffuse senile plaques were found throughout the brain, predominantly in the frontal and temporal lobes, while Alzheimer neurofibrillary tangles were found only in the parahippocampal gyrus. These plaques were positive for beta-protein and mostly negative for tau protein, ubiquitin, neurofilaments, alpha-choline acetyltransferase, and acetylcholinesterase. Mutations in codon 331 of the ND2 gene as well as codons 693, 713 and 717 of the beta-amyloid precursor protein gene, known to be responsible for some cases of familial Alzheimer disease, were not found. Furthermore, coincidental Down syndrome was ruled out by chromosome analysis. The results suggest a possible correlation between this mitochondrial DNA abnormality and Alzheimer-type pathology.
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PMID:Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). 887 Aug 35

Previous observations from several groups suggest that acetylcholinesterase (AChE) may have a role in neural morphogenesis, but not solely by virtue of its ability to hydrolyze acetylcholine. We tested the possibility that AChE influences neurite outgrowth in nonenzymatic ways. With this aim, antisense oligonucleotides were used to decrease AChE levels transiently, and N1E.115 cell lines were engineered for permanently altered AChE protein expression. Cells stably transfected with a sense AChE cDNA construct increased their AChE expression 2.5-fold over the wild type and displayed significantly increased neurite outgrowth. Levels of the differentiation marker, tau, also rose. In contrast, AChE expression in cell lines containing an antisense construct was half of that observed in the wild type. Significant reductions in neurite outgrowth and tau protein accompanied this effect. Overall, these measures correlated statistically with the AChE level (p < 0.01). Furthermore, treatment of AChE-overexpressing cells with a polyclonal antibody against AChE decreased neurite outgrowth by 43%. We conclude that AChE may have a novel, noncholinergic role in neuronal differentiation.
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PMID:Neurite differentiation is modulated in neuroblastoma cells engineered for altered acetylcholinesterase expression. 932 67

An animal model of non-hereditary AD was built by lesioning nucleus basalis of Meynert (nbM) and to investigate the behavioral alteration by Morris water maze, the pathological changes by special staining for senile plaques(SPs), enzymatic cytochemical staining for AChE, and immunocytochemical staining for beta amyloid protein (beta AP) and tau protein. Transmission electron microscopic observation has also been made. Results showed: (1) loss of learning and memory ability; (2) occurrence of necrotic granules in cytoplasm and inclusion in axon hillock; accumulation of necrotic cell, and formation of SPs under light microscope; (3) accumulation of microtubules and formation of inclusion, increase of lysosome and edema and vacuolation of neurons and neuroterminals under electron microscopy; (4) decrease of synaptic density; (5) sharp decrease of AChE (acetylcholinesterase) positive fibers and neurons shown by immunocytochemical staining; (6) overexpression of beta AP and tau protein.
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PMID:[An animal model of non-hereditary Alzheimer's disease and its behavioral and pathologic changes]. 1103 83

The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.
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PMID:Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists. 1112 32

High molecular weight glycosaminoglycans (GAG) and proteoglycans (PG) affect pathological changes of the brain in Alzheimer's disease (AD). PG stimulate the processing and aggregation of amyloid-beta (Abeta), protect the protein from proteolysis, and increase the formation of neurofibrillary tangles by inducing the hyperphosphorylation of tau protein. These effects may be competitively inhibited by GAG. We have studied the effects of orally (by gavage) and subcutaneously (s.c.) administered low molecular weight heparin, C3 (4-10 oligosaccharides; MW = 2.1 kDa; USP value = 12 U/mg), on abnormal tau-2 protein immunoreactivity in the rat hippocampus following a single, unilateral intra-amygdaloid administration of Abeta(25-35). Oral administration of C3 (25 mg/kg; once daily) was initiated 3 days prior to Abeta(25-35) administration, and was continued daily for an additional 14 days. S.c. administration of C3 (2.5 mg/kg, twice daily), was started 3 days prior to, and was continued for 32 days after, Abeta(25-35) administration. Animal brains were subsequently processed for tau-2, ChAT-immunoreactivity, choline acetyltransferase (ChAT) activity and acetylcholinesterase (AChE) activity. Both oral and s.c. administration of C3 attenuated Abeta(25-35) induced appearance of tau-2-immunoreactive (IR) perikarya in the ipsilateral hippocampus (P < 0.05). Hippocampal cholinergic enzyme activity in C3 treated animals was not significantly different from control animals. The present findings suggest that C3 might be used successfully to prevent abnormal tau protein formation in chronic neurologic diseases, such as AD. Moreover, our data demonstrate that the mechanism of this effect does not appear to influence the cholinergic system of the brain.
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PMID:Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Abeta(25-35)-induced abnormal tau protein immunoreactivity in rat brain. 1175 24

The recent development of acetylcholinesterase inhibitors to treat patients with Alzheimer's disease has increased interest in the use of biochemical markers for the early detection and diagnosis of dementia, but only the measurement of the protein 14-3-3 in cerebrospinal fluid (CSF) to help diagnose sporadic Creutzfeldt-Jakob disease has become accepted clinical practice. CSF concentrations of tau protein and beta-amyloid peptide 42 have been widely investigated as potential diagnostic tests for Alzheimer's disease, but neither has shown sufficient sensitivity and specificity for clinical use. Preliminary investigations suggest that beta-amyloid peptide 42 may be useful in monitoring disease progression, but this needs to be verified. In addition, biochemical investigations may help to identify the small number of patients with treatable causes of dementia such as hypothyroidism and vitamin B12 deficiency, as well as any other compounding condition such as anaemia or diabetes mellitus that increase morbidity.
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PMID:Biochemical investigations in patients with dementia. 1203 95

Enormous effort is now being devoted to developing drugs that slow neurodegeneration in Alzheimer's disease (AD), although insights into AD genetics and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase inhibitors that temporarily slow loss of cognitive function remain the only approved AD drugs. Discovery of mutations in three genes leading to severe early onset AD was critical in focusing attention on the role of amyloid peptides (Abeta) in neuronal cell death, and enhanced understanding of the biology of these peptides has led to an array of mechanism-based drug discovery strategies. These include inhibitors for Abeta-generating proteases, agents that prevent or reverse Abeta oligomerization, immunotherapies to reduce Abeta in brain and plasma, and drugs to modulate cholesterol-mediated effects on Abeta transport. Strategies are also underway to minimize toxic effects of Abeta fibrils on neurons, and these include antioxidants, blockers of glutamate-mediated excitotoxicity, and modulators of inflammatory responses within the brain. Although several approaches involve new agents for recently discovered targets, many are based on new applications of existing drugs such as statins and nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated tau protein in neurofibrillary tangles in AD brain has led to strategies for identifying selective inhibitors of tau kinases and central nervous system/brain-permeable drugs that help maintain microtubule integrity. Clearly, a large gap exists between our understanding of the cellular cascades targeted in drug discovery and widespread failure of the nervous system that AD represents. Nevertheless, the pace of recent research clearly supports optimism that slowing progression of AD will soon be possible.
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PMID:Drugs targeting Alzheimer's disease: some things old and some things new. 1260 63

Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and beta-secretase and gamma-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-beta may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.
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PMID:CSF markers for incipient Alzheimer's disease. 1450 82


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