A potent mechanism-inspired O-GIcNAcase inhibitor that blocks phosporylation of tau in vivo

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer’s disease (AD) and theassociated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions inO-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectivelyenhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G,Ki ¼ 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevantsites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 inboth rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylationof tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain,and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.