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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease
Open accessAbstract
The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching of the glycolytic enzyme pyruvate kinase M (PKM) toward the cancer-associated PKM2 isoform conferred metabolic and transcriptional changes in AD iNs. These alterations occurred via PKM2's lack of metabolic activity and via nuclear translocation and association with STAT3 and HIF1α to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 prevented nuclear translocation, restored a mature neuronal metabolism, reversed AD-specific gene expression changes, and re-activated neuronal resilience against cell death.
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“These neurons exhibited several age-associated dysregulations such as instability of mature neuronal fate, increased cellular senescence, and metabolic shifts (11, 24, 25)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [25]
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“but no AD hallmark neuropathology was shown.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [25]
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“Recent studies have directly induced neurons from individuals with AD through NGN2/ASCL1 overexpression.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [25]
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Metadata
- Authors
- Traxler, L., Herdy, J. R., Stefanoni, D., Eichhorner, S., Pelucchi, S., Szücs, A., Santagostino, A., Kim, Y., Agarwal, R. K., Schlachetzki, J. C. M., Glass, C. K., Lagerwall, J., Galasko, D., Gage, F. H., D’Alessandro, A., & Mertens, J.
- Affiliations
- Universität Innsbruck (AT)
- Salk Institute for Biological Studies (US)
- University of Colorado Anschutz (US)
- University of Michigan (US)
- University of California San Diego (US)
- Corresponding author
- Traxler, Larissa
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 34
- Issue
- 9
- Pages
- 1248-1263.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC9458870
- OpenAlex
- W4292379491
- Cited by
- 179
- References
- 70
- Citations by year
- 2026: 35 · 2025: 56 · 2024: 49 · 2023: 29 · 2022: 10
- FWCI
- 22.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- ELTE Digital Institutional Repository (EDIT) (Eötvös Loránd University) (submittedVersion, other-oa)
- Funders
- Alzheimer's Disease Research Center, Emory University (AG062429)
- Leona M. and Harry B. Helmsley Charitable Trust (P30CA23100)
- Marshallplan-Jubiläumsstiftung
- National Institute on Aging (AG056306, AG056511, AG057706)
- BrightFocus Foundation
- European Commission (H2020-MSCA-IF-2017-797205)
- Austrian Science Fund
- Hungarian Scientific Research Fund (ANN-135291)
- European Research Council (ERC-STG-2019-852086)
- Horizon 2020 Marie Skłodowska-Curie Actions
- Milky Way Research Foundation (P30014195)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sporadic Alzheimer's disease, neurodegeneration, aerobic glycolysis, Warburg effect, PKM2, induced neurons, patient-derived fibroblasts, nuclear translocation, STAT3, HIF-1α, neuronal vulnerability, metabolic reprogramming
- MeSH terms
- Alzheimer Disease, Glycolysis, Humans, Neoplasms, Pyruvate Kinase, Protein Isoforms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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