stages of tauopathy by 3 months of age that progress to neurofibrillary degeneration by 8 months. These mice exhibit pathological tau and cognitive dysfunction resembling the changes observed in human AD patients or those with other tauopathy disorders. When combined with the PS19 transgene, MSUT2 gene knockout ameliorates a variety of pathological tau lesions. For instance, MSUT2 KO decreases accumulation of phosphorylated tau (pTau) lesions as represented by immunostaining with AT180, an early marker of pathological tau [20]. Likewise, MSUT2 KO decreased pre-tangle conformations of tau, critical for the eventual formation of mature NFTs [21]. The deposition of tangles is accompanied by obvious neurodegeneration in PS19 Tg mice and MSUT2 KO reduces the tau-mediated loss of neurons in the hippocampus [19]. The amelioration of neurodegeneration is also accompanied by a reduction in astrocytosis as indicated by GFAP staining [19]. We also found MSUT2 KO mice exhibit robust amelioration of tauopathy-related behavioral phenotypes, including a restoration of spatial memory function as detected by the Barnes maze test.
