O1‐06–07: Modulation of Tau phosphorylation and neurofibrillary tangle formation by WWOX

A variety of enzymes are known to hyperphosphorylate tau in vivo. Hyperphosphorylated tau tends to generate paired helical filament (PHF) and neurofibrillary tangles (NFT) in the neurons of patients with Alzheimer's disease (AD). Using both in vitro and in vivo studies we examined the influence of WWOX on AD pathogenesis. In comparison with age-matched normal controls, we determined that WW domain-containing oxidoreductase (WWOX1), its isoform WWOX2, and their Tyr33-phosphorylated forms were significantly down-regulated, which correlates with increased tau and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation, in the neurons of AD hippocampus. In parallel with these clinical findings, suppression of WWOX1 expression by siRNA in cultured HT-22 cells and primary neurons induced the phosphorylation of GSK-3beta and externally regulated kinases/mitogen activated protein kinases (ERKs/MAP kinases), and specifically increased phosphorylation of Tau at Thr231/Thr212. These residues are phosphorylated in the PHF-Tau and NFT. We have shown that WWOX1 physically interacts with tau, JNK1 and GSK-3beta in the extracts of APP/tau tg mouse brains and cultured HT-22 cells, as determined by co-immunoprecipitation. Aβ peptide treatment of HT-22 cells reduced WWOX expression and induced tau hyperphosphorylation and aggregation. Tau was shown to bind to the COOH-terminal short-chain alcohol dehydrogenase/reductase domain (ADH) of WWOX and tau phosphorylation was inhibited. Synthetic peptides corresponding to the ADH domain blocked tau phosphorylation and NFT formation in vitro. WWOX1 deficiency in the APP/tau mutant mice exacerbated both the Aβ and tau pathology in these animals. Together, these studies suggest a functional role for WWOX1 in regulating tau hyperphosphorylation and subsequent NFT formation in AD and possibly provide a target for therapeutic intervention.