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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main pathological features of Alzheimer's disease are Alzheimer neurofibrillary tangles and senile plaques. Recent biochemical research revealed that tangles are composed of tau protein and ubiquitin and amyloid in senile plaques is composed of beta protein which is a fragment of the membrane receptor protein. Although fraction, other data suggest that whole molecules become abnormal and aggregate into PHF. On the other hand, beta protein is a small cleavage product of the precursor protein. It is not concluded yet whether abnormal precursor proteins exist or not. Recent research in this field is reviewed.
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PMID:[Tau protein and beta protein]. 212 Apr 89

Deposition of large quantities of amyloid substance in the walls of the cerebral vessels and in the core of the senile plaques is characteristic of Alzheimer's disease. beta A4 peptide, the main component of the amyloid substance, is a product of a larger amyloid precursor protein which has the structure of a transmembrane receptor and is widely distributed throughout the body. The pathway leading to beta A4 is not yet fully established but could involve lysosomal degradation. It has been suggested that the beta A4 peptide is of neuronal or vascular origin. The beta A4 peptide is found in diffuse deposits in the cortex and cerebellum as well as in the basal ganglia before the classic senile plaques appear, mainly in layer III of the cerebral cortex. These diffuse deposits are devoid of degenerating neurites (i.e. containing abnormally phosphorylated tau protein). The classical senile plaques contain numerous degenerating neurites linking them to the connective network of the cortex. The intellectual deficit is correlated significantly to the density of the classical senile plaques but not to the density of the diffuse deposits. Although a mutation of the gene coding for the beta A4 peptide appears to be sufficient to induce (or accelerate) Alzheimer's disease, this is undoubtedly an exceptional mechanism. Certain mutations involving the beta A4 precursor protein gene increase in vitro the production of beta A4. The molecular and morphological steps leading, from the accumulation of the peptide (which in itself has no clinical expression) to the neurofibrillary pathology of the senile plaques and of the neurones (which are strongly correlated with clinical dementia), remain hypothetical.
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PMID:[Alzheimer disease. Role of beta A4 peptide and cerebral amyloid substance]. 793 6

Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43-residue peptide (termed A beta), which is derived from a 695- to 770-amino-acid precursor protein (termed beta PP). The main component of PHFs identified so far is the microtubule-associated protein tau. Yet, there is no direct evidence of interconnection between these two pathological states. We report here that antibodies to an epitope located between residues 713 and 723 of beta PP770 (ie, the transmembrane region of beta PP distal to A beta) consistently labeled PHFs in the brain of Alzheimer patients. Solid phase immunoassay showed that a peptide homologous to residues 713 to 730 of beta PP770 bound tau proteins. This beta PP peptide spontaneously formed fibrils in vitro and, in the presence of tau, generated dense fibrillary assemblies containing both molecules. These data suggest that beta PP or beta PP fragments containing the tau binding site are involved in the pathogenesis of PHFs in Alzheimer's disease.
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PMID:beta PP and Tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease. 854 29

In transgenic mice that overexpress mutant Amyloid Precursor Protein [V717I], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mice that overexpress different mutants of Amyloid Precursor Protein in brain. J. Biol. Chem. 274, 6483-6492; 1999b. Premature death in transgenic mice that overexpress mutant Amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91, 819-830) the AD related phenotype of plaque and vascular amyloid pathology is late (12-15 months). This typical and diagnostic pathology is thereby dissociated in time from early symptoms (3-9 months) that include disturbed behavior, neophobia, aggression, glutamate excitotoxicity, defective cognition and decreased LTP. The APP/Lo transgenic mice are therefore a very interesting model to study early as well as late pathology, including the effect of age. In ageing APP*Lo mice, brain soluble and especially "insoluble" amyloid peptides dramatically increased, while normalized levels of secreted APPsalpha and APPsbeta, as well as cell-bound beta-C-stubs, remained remarkably constant, indicating normal alpha- and beta-secretase processing of APP. In double transgenic mice, i.e. APP/LoxPS1, clinical mutant PS1[A246E] but not wild-type human PS1 increased Abeta, and plaques and vascular amyloid developed at age 6-9 months. The PS1 mutant caused increasing Abeta42 production, while ageing did not. Amyloid deposits are thus formed, not by overproduction of Abeta, but by lack of clearance and/or degradation in the brain of ageing APP/Lo transgenic mice. The clearance pathways of the cerebral amyloid peptides are therefore valuable targets for fundamental research and for therapeutic potential. Although hyper-phosphorylated protein tau was evident in swollen neurites around the amyloid plaques, neurofibrillary pathology is not observed and the "tangle" aspect of AD pathology is therefore still missing from all current transgenic "amyloid" models. Also the "ApoE4" risk for late onset AD remains a problem for modeling in transgenic mice. We have generated transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein tau in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951-964) or human protein tau (1999. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153-2165) in their neurons. Both develop a similar although not identical axonopathy, with progressive degeneration of nerves and with muscle wasting resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, like the tau transgenic mice, characterized by progressive hyper-phosphorylation of protein tau also in motor neurons which explains the motoric defects. Further crossing with the APP/Lo transgenic mice is ongoing to yield "multiple" transgenic mouse strains to study new aspects of amyloid and tau pathology.
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PMID:Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. 1105 74

We review the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM) and present the pathologic diagnostic criteria of s-IBM. We discuss the possible pathogenic role of several themes, such as 1) increased amyloid-beta precursor protein (AbetaPP) and of its fragment Abeta; 2) phosphorylation of tau protein; 3) oxidative stress; 4) abnormal a) signal-transduction, b) transcription, and c) RNA accumulation; 5) "junctionalization" and myogenous" denervation; and 6) lymphocytic inflammation. Evidence is provided supporting our hypothesis that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease (AD) brain are discussed, and the possible cause and significance are addressed.
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PMID:Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. 1120 70

Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.
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PMID:Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. 1189 40

The objective of this study was to investigate whether microtubular structure changes and tau protein hyperphosphorylation exist in hippocampal neurons of experimental diabetic mice, and to study the effect of amyloid precursor protein 17mer peptide. The results showed that the microtubules of hippocampal neurons of diabetic mice manifested prominent signs of fragmentation and dissolution, tau protein is hyperphosphorylated at Ser 199/Thr 202 sites, enzymes related to the phosphorylation and dephosphorylation of tau protein were diminished. The administration of amyloid precursor protein 17mer peptide could ameliorate the foregoing changes in diabetic mice. These results indicated that protein synthesis in the brain tissue of diabetic mice decreased. Amyloid precursor protein 17mer peptide acted as a neuroprotective agent that globally alleviates the disturbances due to impaired energy metabolism in diabetic mice.
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PMID:Effect of amyloid precursor protein 17mer peptide on microtubule structure and tau protein hyperphosphorylation in hippocampal neurons of experimental diabetic mice. 1254 32

Amyloid-beta, a peptide derived from the precursor protein APP, accumulates in the brain and contributes to the neuropathology of Alzheimer's disease. Increased generation of amyloid-beta might be caused by axonal transport inhibition, via increased dwell time of APP vesicles and thereby higher probability of APP cleavage by secretase enzymes residing on the same vesicles. We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged APP and beta-secretase (BACE1). Microtubule-associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks. In neurons co-transfected with CFP-tau, APP-YFP traffic into distal neurites was strongly reduced. However, this did not increase amyloid-beta levels. In singly transfected axons, APP-YFP was transported in large tubules and vesicles moving very fast (on average 3 microm/s) and with high fluxes in the anterograde direction (on average 8.4 vesicles/min). By contrast, BACE1-CFP movement was in smaller tubules and vesicles that were almost 2x slower (on average 1.6 microm/s) with approximately 18x lower fluxes (on average 0.5 vesicles/min). Two-colour microscopy of co-transfected axons confirmed that the two proteins were sorted into distinct carriers. The results do not support the above hypothesis. Instead, they indicate that APP is transported on vesicles distinct from the secretase components and that amyloid-beta is not generated in transit when transport is blocked by tau.
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PMID:Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides. 1673 69

Progress in understanding and treating Alzheimer's disease (AD) has been tremendously bolstered by the era of transgenic models of AD. The identification of disease-causing mutations in proteins such as amyloid-beta precursor protein (betaAPP) and presenilin1 (PS1), together with the discovery of other high risk factors (e.g., Apolipoprotein E4), as well as pathogenic mutations in the tau protein has led to the creation of several transgenic mice, including those expressing bi- and tri-genic constructs. Each model has unique pathologies that provide insights into disease mechanisms and interactive features of neuropathologic cascades. More importantly, therapeutic hypotheses are now testable in a manner unheard of less than 15 years ago. The wealth of new approaches currently in clinical and preclinical evaluations can be directly attributed to the impact of these animals on our ability to model relevant aspects of the disease. As a result, we may see containment or even the elimination of AD in the near future as a direct consequence of these advances.
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PMID:Mice as models: transgenic approaches and Alzheimer's disease. 1691 52

Alzheimer's Disease (AD) is characterized by amyloid plaques consisting of beta-amyloid (Abeta) peptides and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Abeta is proteolytically derived from its precursor protein through cleavages by beta-secretase and gamma-secretase complex comprising presenilins (PS, PS1/PS2), nicastrin, APH-1 and PEN-2. PS1 is also known to activate the PI3K/Akt cell survival pathway in a gamma-secretase-independent manner. The tumor suppressor PTEN, which antagonizes the PI3K/Akt pathway, has increasingly been recognized to play a key role in neural functions and its level found reduced in AD brains. Here, we demonstrate that the protein level of PTEN is dramatically reduced in cultured cells and embryonic tissues deficient in PS, and in the cortical neurons of PS1/PS2 conditional double knockout mice. Restoration of PS in PS-deficient cells reverses the reduction of PTEN. Regulation of PTEN by PS is independent of the PS/gamma-secretase activity since impaired gamma-secretase by the gamma-secretase inhibitor treatment or due to nicastrin deficiency has little effect on the protein level of PTEN. Our data suggest an important role for PS in signaling pathways involving PI3K/Akt and PTEN that are crucial for physiological functions and the pathogenesis of multiple diseases.
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PMID:Presenilins regulate the cellular level of the tumor suppressor PTEN. 1722 49


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