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Cell Rep. 2015 May 5;11(5):689-96. doi: 10.1016/j.celrep.2015.03.068. Epub 2015 Apr 23.

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Author information

1
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
2
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
3
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden.
4
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK.
5
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.
6
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.

Abstract

Accumulation of Aβ 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 Aβ 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 β-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 Aβ signaling to neurons.

PMID:
25921538
PMCID:
PMC4431668
DOI:
10.1016/j.celrep.2015.03.068
[Indexed for MEDLINE]
Free PMC Article

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