APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons.
Open accessAbstract
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.
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The reduction in amyloid beta production by NB-360 in oligodendrocytes is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors.
“Notably, this reduction in Aβ production is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors [21–24]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [24]
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- Authors
- Moore, S., Evans, L. D. B., Andersson, T., Portelius, E., Smith, J., Dias, T. B., Saurat, N., McGlade, A., Kirwan, P., Blennow, K., Hardy, J., Zetterberg, H., & Livesey, F. J.
- Affiliations
- University of Cambridge (GB)
- Stockholm University (SE)
- University of Gothenburg (SE)
- UCL Queen Square Institute of Neurology (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Livesey, Frederick J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 11
- Issue
- 5
- Pages
- 689-696
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4431668
- OpenAlex
- W2083922876
- Cited by
- 179
- References
- 30
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 21 · 2020: 28 · 2019: 27 · 2018: 21 · 2017: 20 · 2016: 12 · 2015: 13
- FWCI
- 16.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (101052, 97922, 092096)
- Cancer Research UK
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (MR/L023784/1, MR/L023784/2)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APP metabolism, Alzheimer's disease, amyloid-beta, tau phosphorylation, APP mutations, forebrain neurons, stem cell-derived neurons, beta-secretase inhibition, gamma-secretase inhibition
- MeSH terms
- Alzheimer Disease, Cerebral Cortex, Humans, Neurons, Phosphorylation, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Gene Dosage, Amino Acid Substitution, Amyloid Precursor Protein Secretases
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