APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

•Neurons from different genetic forms of Alzheimer’s disease differ in APP processing•APP mutations increase total and phosphorylated tau; PSEN1 mutations do not•Pharmacological manipulation of APP processing changes tau protein levels•APP regulation of tau proteostasis is not solely mediated through extracellular Aβ

SummaryAccumulation 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.

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