Journal
CELL METABOLISM
Volume 34, Issue 9, Pages 1248-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2022.07.014
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Funding
- EU
- H2020-MSCA-IF-2017
- BrightFocus Foundation
- Austrian Marshall Plan Foundation
- Shiley -Marcos Alzheimer's Disease Research Center (ADRC) at UCSD
- National Brain Research Program of Hungary
- Hungarian Scientific Research Foundation [852086]
- Austrian Science Fund [797205]
- AHA-Allen Initiative award
- Paul G. Allen Family Foundation
- NIA R01s [AG062429]
- JPB Foundation [2017-1.2.1-NKP-2017-00002]
- Ray and Dagmar Dolby Family Fund [ANN -135291]
- Milky Way Research Foundation [FWF I-5057]
- NGS Core Facility [19PABH134610000]
- Flow Cytometry Core Facility of the Salk Institute
- NIH-NCI [AG056306, AG056511, AG057706]
- Chapman Foundation
- Helmsley Charitable Trust
- CCSG
- [CCSG:P30014195]
- [P30CA23100]
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This study investigated the metabolic changes and transcriptional alterations in sporadic Alzheimer's disease (AD) utilizing induced neurons (iNs) from AD patients. The pathological isoform switching of PKM2 was found to contribute to neuronal vulnerability and loss in AD. Chemical modulation of PKM2 could reverse these changes and enhance neuronal resilience against cell death.
The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly con-verted 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 HIF1a to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 pre-vented 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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