Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease

Larissa Traxler; Joseph R Herdy; Davide Stefanoni; Sophie Eichhorner; Silvia Pelucchi; Attila Szücs; Alice Santagostino; Yongsung Kim; Ravi K Agarwal; Johannes C M Schlachetzki; Christopher K Glass; Jessica Lagerwall; Douglas Galasko; Fred H Gage; Angelo D'Alessandro; Jerome Mertens

doi:10.1016/j.cmet.2022.07.014

Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease

Cell Metab. 2022 Sep 6;34(9):1248-1263.e6. doi: 10.1016/j.cmet.2022.07.014. Epub 2022 Aug 19.

Authors

Larissa Traxler¹, Joseph R Herdy², Davide Stefanoni³, Sophie Eichhorner⁴, Silvia Pelucchi⁴, Attila Szücs⁵, Alice Santagostino⁴, Yongsung Kim⁶, Ravi K Agarwal⁷, Johannes C M Schlachetzki⁸, Christopher K Glass⁸, Jessica Lagerwall⁴, Douglas Galasko⁹, Fred H Gage⁷, Angelo D'Alessandro³, Jerome Mertens¹⁰

Affiliations

¹ Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University, Innsbruck 6020, Austria. Electronic address: larissa.traxler@uibk.ac.at.
² Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University, Innsbruck 6020, Austria; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
³ Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁴ Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University, Innsbruck 6020, Austria.
⁵ Neuronal Cell Biology Research Group, Eötvös Loránd University, Budapest 1117, Hungary.
⁶ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-5624, USA.
⁷ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
⁹ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, USA.
¹⁰ Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University, Innsbruck 6020, Austria; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: jerome.mertens@uibk.ac.at.

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.

Keywords: Alzheimer's disease; WGCNA; Warburg effect; cancer; direct conversion; induced neurons; metabolomics; pyruvate kinase M; reprogramming.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Glycolysis
Humans
Neoplasms* / pathology
Protein Isoforms / genetics
Protein Isoforms / metabolism
Pyruvate Kinase / genetics
Pyruvate Kinase / metabolism

Substances

Protein Isoforms
Pyruvate Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding