APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

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Evans, Lewis DB 
Andersson, Therese 
Portelius, Erik 

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.

Alzheimer Disease, Amino Acid Substitution, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cerebral Cortex, Gene Dosage, Humans, Neurons, Phosphorylation, Signal Transduction, tau Proteins
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European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (115439)
Wellcome Trust (101052/Z/13/Z)
Medical Research Council (MR/L023784/2)
Medical Research Council (MR/L023784/1)
This research was supported by grants from Alzheimer’s Research UK and the Wellcome Trust (to F.J.L.) and core funding to the Gurdon Trust from the Wellcome Trust and Cancer Research UK. N.S. was supported by a Woolf-Fisher Trust (NZ) PhD studentship. H.Z. was supported by the Wolfson Centre at UCL, and the UCLH Dementia BRU provided financial support for the collection of patient materials. F.J.L. is a Wellcome Trust Senior Investigator, K.B. is a Torsten So¨ derberg Academy Professor, and H.Z. is a Wallenberg Academy Fellow.