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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease
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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458870/ https://www.ncbi.nlm.nih.gov/pubmed/35987203 http://dx.doi.org/10.1016/j.cmet.2022.07.014 |
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author | Traxler, Larissa Herdy, Joseph R. Stefanoni, Davide Eichhorner, Sophie Pelucchi, Silvia Szücs, Attila Santagostino, Alice Kim, Yongsung Agarwal, Ravi K. Schlachetzki, Johannes C.M. Glass, Christopher K. Lagerwall, Jessica Galasko, Douglas Gage, Fred H. D’Alessandro, Angelo Mertens, Jerome |
author_facet | Traxler, Larissa Herdy, Joseph R. Stefanoni, Davide Eichhorner, Sophie Pelucchi, Silvia Szücs, Attila Santagostino, Alice Kim, Yongsung Agarwal, Ravi K. Schlachetzki, Johannes C.M. Glass, Christopher K. Lagerwall, Jessica Galasko, Douglas Gage, Fred H. D’Alessandro, Angelo Mertens, Jerome |
author_sort | Traxler, Larissa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9458870 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-94588702022-09-09 Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease Traxler, Larissa Herdy, Joseph R. Stefanoni, Davide Eichhorner, Sophie Pelucchi, Silvia Szücs, Attila Santagostino, Alice Kim, Yongsung Agarwal, Ravi K. Schlachetzki, Johannes C.M. Glass, Christopher K. Lagerwall, Jessica Galasko, Douglas Gage, Fred H. D’Alessandro, Angelo Mertens, Jerome Cell Metab Article 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. Cell Press 2022-09-06 /pmc/articles/PMC9458870/ /pubmed/35987203 http://dx.doi.org/10.1016/j.cmet.2022.07.014 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Traxler, Larissa Herdy, Joseph R. Stefanoni, Davide Eichhorner, Sophie Pelucchi, Silvia Szücs, Attila Santagostino, Alice Kim, Yongsung Agarwal, Ravi K. Schlachetzki, Johannes C.M. Glass, Christopher K. Lagerwall, Jessica Galasko, Douglas Gage, Fred H. D’Alessandro, Angelo Mertens, Jerome Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title | Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title_full | Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title_fullStr | Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title_full_unstemmed | Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title_short | Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease |
title_sort | warburg-like metabolic transformation underlies neuronal degeneration in sporadic alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458870/ https://www.ncbi.nlm.nih.gov/pubmed/35987203 http://dx.doi.org/10.1016/j.cmet.2022.07.014 |
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