Sympathetic overactivity-induced type H endothelial cell senescence contributes to the impairment of vascularized osteogenesis by PKM2-mediated glycolysis in preclinical stages of Alzheimer's mice.

Alzheimer's disease (AD) is characterized by early-onset bone loss, yet the underlying mechanisms remain elusive. Here, we demonstrated that sympathetic hyperactivity drives vascularized osteogenesis impairment in preclinical AD through a novel PKM2-glycolysis-mediated bone vascular endothelial cell (EC) senescence pathway. Utilizing systematic transcriptome profiling complemented by in vitro functional assays and in vivo validation studies, we found that norepinephrine (NE)-induced PKM2 downregulation disrupts glycolytic flux, triggering mitochondrial dysfunction-induced senescence (MiDAS) in vascular ECs. This metabolic reprogramming of vascular ECs inhibits the differentiation of osteoprogenitors by reducing the secretion of pro-osteogenic factors. Pharmacological inhibition of β-adrenergic signaling or PKM2 activation rescues EC senescence and bone loss. Mechanistically, NE released by the sympathetic nerve suppresses c-Maf, a transcription factor critical for PKM2 expression, linking sympathetic activation to metabolic dysfunction. Furthermore, our results also showed that combination therapy with oryzanol (sympathetic modulator) and eldecalcitol (senolytic) synergistically restores vascularized osteogenesis by targeting both neurovascular and metabolic axes. These findings establish a pathogenic role for sympathetic hyperactivity in AD-related skeletal dysfunction and highlight a therapeutic strategy targeting EC senescence and glycolytic metabolism.