1. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease.
- Author
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Traxler L, Herdy JR, Stefanoni D, Eichhorner S, Pelucchi S, Szücs A, Santagostino A, Kim Y, Agarwal RK, Schlachetzki JCM, Glass CK, Lagerwall J, Galasko D, Gage FH, D'Alessandro A, and Mertens J
- Subjects
- Glycolysis, Humans, Protein Isoforms genetics, Protein Isoforms metabolism, Pyruvate Kinase genetics, Pyruvate Kinase metabolism, Alzheimer Disease, Neoplasms pathology
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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