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.

Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease / L. Traxler, J.R. Herdy, D. Stefanoni, S. Eichhorner, S. Pelucchi, A. Szücs, A. Santagostino, Y. Kim, R.K. Agarwal, J.C.M. Schlachetzki, C.K. Glass, J. Lagerwall, D. Galasko, F.H. Gage, A. D’Alessandro, J. Mertens. - In: CELL METABOLISM. - ISSN 1550-4131. - 34:9(2022), pp. 1248-1263. [10.1016/j.cmet.2022.07.014]

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

S. Pelucchi;
2022

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.
Alzheimer's disease; WGCNA; Warburg effect; cancer; direct conversion; induced neurons; metabolomics; pyruvate kinase M; reprogramming
Settore BIO/14 - Farmacologia
   Assessing transcriptional and nuclear pore aging in age-equivalent and rejuvenated induced neurons from Alzheimer patients
   iNtoPoreAge
   European Commission
   Horizon 2020 Framework Programme
   797205

   Age-dependent mechanisms of sporadic Alzheimer’s Disease in patient-derived neurons
   AGEMEC
   European Commission
   Horizon 2020 Framework Programme
   852086
2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1027293
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