APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

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.

• Authors: Steven Moore, Lewis D B Evans, Therese Andersson, Erik Portelius, James Smith, Tatyana B Dias, Nathalie Saurat, Amelia McGlade, Peter Kirwan, Kaj Blennow, John Hardy, Henrik Zetterberg, Frederick J Livesey
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 5 Pg. 689-96 (May 05 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 25921538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• tau Proteins
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (metabolism, pathology)
• Amino Acid Substitution
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Cerebral Cortex (metabolism)
• Gene Dosage
• Humans
• Neurons (metabolism)
• Phosphorylation
• Signal Transduction
• tau Proteins (metabolism)