APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

作者：Moore Steven; Evans Lewis D B; Andersson Therese; Portelius Erik; Smith James; Dias Tatyana B; Saurat Nathalie; McGlade Amelia; Kirwan Peter; Blennow Kaj; Hardy John; Zetterberg Henrik; Livesey Frederick J^*

来源：Cell Reports, 2015, 11(5): 689-696.

DOI：10.1016/j.celrep.2015.03.068

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.

• 出版日期2015-5-5