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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2022
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.
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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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