Impact of Klotho genotype on lactylation in Alzheimer’s disease and mechanistic insights

Protein lactylation has emerged as a crucial regulator in the pathogenesis of Alzheimer’s disease (AD). Although the Klotho gene (KL) has been clinically linked to AD, its role in lactylation remains unclear. Here, we investigated the influence of Klotho genotype on lactylation and related inflammatory responses. Wild-type KL and the KL F352V variant were transfected into microglia and BV-2 cells of an AD model to assess effects on protein lactylation and cytokine release, followed by transcriptome sequencing to identify downstream mediators. Functional validation using qPCR, ELISA, Western blotting, and immunohistochemistry confirmed that KL expression markedly reduced lactylated protein levels and pro-inflammatory factors, while ameliorating pathological features in AD model mice. Transcriptomic analysis highlighted oncostatin M (OSM) as a key gene suppressed by KL, and OSM knockdown decreased both protein lactylation and inflammation, improving AD pathology in vivo. These findings demonstrate that KL protects against AD progression by inhibiting OSM-mediated signaling, thereby attenuating lactylation and neuroinflammation, and provide novel mechanistic insight into the genetic regulation of lactylation in neurodegeneration.