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 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. [Display omitted] •iNs from patients with AD express cancer-associated PKM2•PKM2 facilitates Warburg-effect-like glycolytic reprogramming of old neurons•Nuclear PKM2 associates with STAT3 and HIF1α to promote neuronal fate loss in AD iNs•Modulation of PKM2 with shikonin restores healthy neuronal features Traxler et al. discover that the metabolic and epigenetic regulator PKM2 is expressed in the brain tissues from patients with Alzheimer’s disease and in patient-derived induced neurons. Neuronal PKM2 causes a metabolic shift, fate loss, and apoptotic competency, which could be partially ameliorated with the PKM2 modulator shikonin, indicating the potential for the therapeutic targeting of PKM2 for age-related neurodegeneration.