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APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

Moore, S. (author)
Evans, L. D. B. (author)
Andersson, Therese (author)
Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
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Portelius, Erik, 1977 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Smith, J. (author)
Dias, T. B. (author)
Saurat, N. (author)
McGlade, A. (author)
Kirwan, P. (author)
Blennow, Kaj, 1958 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Hardy, J. (author)
Zetterberg, Henrik, 1973 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Livesey, F. J. (author)
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 (creator_code:org_t)
Elsevier BV, 2015
2015
English.
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 11:5, s. 689-696
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Accumulation of A beta 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 A beta 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 beta-secretase and gamma-secretase inhibition, as well as gamma-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 A beta signaling to neurons.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)
NATURVETENSKAP  -- Biologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Keyword

PLURIPOTENT STEM-CELLS
FAMILIAL ALZHEIMERS-DISEASE
A-BETA
PROTEIN
DUPLICATION
FRAGMENT
LOCUS
Cell Biology

Publication and Content Type

ref (subject category)
art (subject category)

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