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 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.

Automated summary

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.