APP metabolism regulates tau proteostasis in human cerebral cortex neurons.
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.
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Steven
S
Moore
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Lewis D B
LD
Evans
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
Therese
T
Andersson
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden.
Erik
E
Portelius
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
James
J
Smith
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Tatyana B
TB
Dias
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Nathalie
N
Saurat
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Amelia
A
McGlade
The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
Peter
P
Kirwan
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, Sweden.
Kaj
K
Blennow
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UK.
John
J
Hardy
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.
Henrik
H
Zetterberg
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.
Frederick J
FJ
Livesey
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D018628:Gene Dosage; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases