Inhibiting a glycolysis positive feedback loop in Alzheimer's

Inhibiting the glycolysis regulator PKM2, whose activity results in elevated lactate levels that promote histone lactylation and downstream expression of glycolysis genes via a positive feedback loop, could help treat AD.

In postmortem brain tissue samples, pan-lysine lactylation and H4K12la levels were increased in AD patients compared with healthy controls. In a mouse microglial cell culture, shRNA knockdown or pharmacological inhibition of PKM2 decreased levels of intracellular lactate, pan-lysine lactylation, H4K12la modifications on glycolytic gene promoters, and expression of those glycolytic genes compared with normal expression or vehicle, respectively...