Journal
CELL REPORTS
Volume 11, Issue 5, Pages 689-696Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.03.068
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Funding
- Alzheimer's Research UK
- Wellcome Trust
- Cancer Research UK
- Woolf-Fisher Trust (NZ)
- Wolfson Centre at UCL
- UCLH Dementia BRU
- Alzheimers Research UK [ART-PG2011-17] Funding Source: researchfish
- MRC [MR/L023784/2, MR/L023784/1] Funding Source: UKRI
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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.
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