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 immunolocalization of presenilin in human brain was studied using two antibodies raised against different portions of presenilin 1 (S182) protein. A granular staining was found in the cytoplasm of neurons in cortical layers III and V. One of the antibodies, also reactive to presenilin 2 (E5-1) protein, additionally stained dendrites and axons. This was seen in normal brains as well as in brains affected by Alzheimer's disease. Less prominent immunolabeling was noted in some senile plaques. No relationship to neurofibrillary tangles was found in double-labeling experiments combined with anti-paired helical filament-tau antibody (AT8). The widespread expression of presenilin in normal brain suggests a physiological role of the protein.
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PMID:Widespread immunoreactivity of presenilin in neurons of normal and Alzheimer's disease brains: double-labeling immunohistochemical study. 889 Oct 63

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

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid beta protein (Abeta1-42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3beta (GSK-3beta). Deletion studies show that both tau and GSK-3beta bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3beta into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3beta. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3beta with mutant PS1 leads to increased phosphorylation of tau.
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PMID:Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. 968 33

Alzheimer's disease (AD) is neuropathologically marked by the presence of senile plaques composed of beta-amyloid peptide and by neurofibrillary tangles formed by abnormally phosphorylated tau protein. Many authors have also reported a neuronal loss in affected regions of the brain in AD patients. This neuronal degeneration could be linked to the triggering of intracellular pathways leading to apoptosis. Previous works were focused on the links between neuronal apoptosis and tau and amyloid precursor protein (APP) metabolisms. We have analyzed tau gene expression in primary neuronal cultures submitted to an apoptotic stress produced by excitotoxicity or serum deprivation. Glutamate induces an enhancement of tau gene expression in resistant neurons whereas a reduced expression is noted in apoptotic cells. This decrease is similar to what is observed after trophic support withdrawal in neuronal cultures. Neurons expressing phosphorylated tau are more resistant to experimental apoptosis than neurons positively labeled for dephosphorylated tau protein (AT8/Tau 1 epitope). In vitro apoptotic neurons are able to produce membrane blebbings (strongly immunopositive for APP and amyloidogenic fragments) that are secondary released in the extracellular space. Finally neurons overexpressing human mutated presenilin 1 (M146 L) are more prone to degenerate than neurons overexpressing human wild-type presenilin 1 after apoptosis induction.
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PMID:Markers of apoptosis and models of programmed cell death in Alzheimer's disease. 1096 25

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.
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PMID:Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. 1137 23

Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with beta-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated alpha-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 beta (GSK-3 beta) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3 beta distribution showing that developmental evolution of GSK-3 beta compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 beta activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing beta-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation.
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PMID:Neurofibrillary tangles and tau phosphorylation. 1144 42

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule-associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick-type tauopathy in the absence of extracellular beta-amyloid deposits. The mutation is predicted to substitute Gly-->Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical-genetic investigation showed a positive family history of FTD-like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick-type tauopathy without MAPT mutations.
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PMID:A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. 1512 99

Like several other adult onset neurodegenerative diseases, Alzheimer's disease is a multifactorial illness with both genetic and non-genetic causes. Recent genetic studies have identified four genes associated with inherited risk for AD (presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E). These genes account for about half of the total genetic risk for Alzheimer's disease. It is suspected that several other Alzheimer's disease-susceptibility genes exist, and their identification is the subject of ongoing research. Nevertheless, biological studies on the effects of mutations in the four known genes has led to the conclusion that all of these genes cause dysregulation of amyloid precursor protein processing and in particular dysregulation of the handling of a proteolytic derivative termed Abeta. The accumulation of Abeta appears to be an early and initiating event that triggers a series of downstream processes including misprocessing of the tau protein. This cascade ultimately causes neuronal dysfunction and death, and leads to the clinical and pathological features of Alzheimer's disease. Knowledge of this biochemical cascade now provides several potential targets for the development of diagnostics and therapeutics.
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PMID:Molecular biology and genetics of Alzheimer's disease. 1577 Sep 98

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer's disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.
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PMID:Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. 1654 71

We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons. Mutation screening that included all coding exons of presenilin 1 (PSEN1), presenilin 2 (PSEN2), alpha-synuclein (SNCA), beta-synuclein (SNCB), microtubule-associated protein tau (MAPT), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and exons 16 and 17 of the amyloid precursor protein (APP) genes did not identify any mutation. Genome-wide single nucleotide polymorphism was performed in 4 family members and ruled out any pathogenic duplication or deletion in the entire genome. In summary, we report a unique family with pathologically confirmed early-onset dementia with Lewy bodies with widespread tau and alpha-synuclein deposition. The absence of mutations in genes known to cause Lewy body disease suggests that a novel locus or loci are implicated in this neurodegenerative disease.
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PMID:Early-onset familial lewy body dementia with extensive tauopathy: a clinical, genetic, and neuropathological study. 1910 44


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