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APP metabolism regulates tau proteostasis in human cerebral cortex neurons.
Moore, Steven; Evans, Lewis D B; Andersson, Therese; Portelius, Erik; Smith, James; Dias, Tatyana B; Saurat, Nathalie; McGlade, Amelia; Kirwan, Peter; Blennow, Kaj; Hardy, John; Zetterberg, Henrik; Livesey, Frederick J.
Afiliación
  • Moore S; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Evans LD; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Andersson T; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
  • Portelius E; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden.
  • Smith J; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Dias TB; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Saurat N; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • McGlade A; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Kirwan P; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden.
  • Hardy J; Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK.
  • Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden; Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK.
  • Livesey FJ; The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: rick@gurdon.cam.ac.uk.
Cell Rep ; 11(5): 689-96, 2015 May 05.
Article en En | MEDLINE | ID: mdl-25921538
Accumulation of Aß peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aß peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by ß-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aß signaling to neurons.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Corteza Cerebral / Precursor de Proteína beta-Amiloide / Proteínas tau / Neuronas Límite: Humans Idioma: En Revista: Cell Rep Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Corteza Cerebral / Precursor de Proteína beta-Amiloide / Proteínas tau / Neuronas Límite: Humans Idioma: En Revista: Cell Rep Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos