APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

• Published in: Cell reports (Cambridge) 2015-05, Vol.11 (5), p.689-696
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: A-BETA; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amino Acid Substitution; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Cell and Molecular Biology; Cell Biology; Cell- och molekylärbiologi; Cerebral Cortex - metabolism; DUPLICATION; FAMILIAL ALZHEIMERS-DISEASE; FRAGMENT; Gene Dosage; Humans; LOCUS; Neurons - metabolism; Neurosciences; Neurovetenskaper; Phosphorylation; PLURIPOTENT STEM-CELLS; PROTEIN; Signal Transduction; tau Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.03.068

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. [Display omitted] •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 Moore et al. use neurons made from familial Alzheimer’s disease stem cells to reveal how three proteins involved in the disease are linked in a pathway that controls disease progression. They show that drugs that target this pathway change levels of a protein involved in neurodegeneration, microtubule-associated protein tau, opening up a potential therapeutic pathway.