Histologic scoring was based on a previously described method. Briefly, hematoxylin and eosin-stained cross-sections of the descending colon tissue were scored microscopically in a blinded fashion on a scale from 0�C4 based on the following histologic criteria: 0, no change from normal tissue; 1, low level of inflammation with scattered infiltrating mononuclear cells; 2, moderate inflammation with multiple foci; 3, high level of inflammation with increased vascular density and marked wall thickening; 4, maximal severity of inflammation with transmural leukocyte infiltration and loss of goblet cells. An average of four fields of view per colon were evaluated for each mouse. These scores were averaged for each group and recorded as the histopathology score. Microtubule-associated protein tau is a cytosolic protein that stimulates microtubule assembly and stabilizes microtubule structure. The integrity of the microtubule system is essential for the transport of materials between the cell body and synaptic terminals of neurons. The microtubule system is disrupted and replaced by the accumulation of highly phosphorylated tau as neurofibrillary tangles in affected neurons in the brains of individuals with Alzheimer diseaseand other neurodegenerative disorders collectively called tauopathies. Neurofibrillary tangles are also one of the hallmark histopathological lesions of AD brain. Many studies have demonstrated the critical role of hyperphosphorylation and aggregation of tau in neurodegeneration in AD and other tauopathies. The abnormal hyperphosphorylation may cause dissociation of tau from microtubules and, consequently, raise intracellular tau concentration enough to initiate its polymerization into neurofibrillary tangles. The mechanisms by which tau becomes abnormally hyperphosphorylated in AD and other ABT-199 Bcl-2 inhibitor tauopathies are not well understood. Many studies have demonstrated that in the brain, tau phosphorylation is mainly controlled by the kinases glycogen synthase kinase-3band cyclin-dependent protein kinase 5 as well as protein phosphatase 2A. A down-regulation of PP2A in AD brain was found by our and other groups, suggesting that this decrease may be partially responsible for the abnormal hyperphosphorylation of tau in AD. It was demonstrated recently that tau phosphorylation is negatively regulated by O-GlcNAcylation, a posttranslational modification of proteins with b-N-acetylglucosamine. Like protein phosphorylation, Niraparib PARP inhibitor O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase, the enzyme catalyzing the transfer of GlcNAc from UDP-GlcNAc donor onto proteins, and N-acetylglucosaminidase, the enzyme catalyzing the removal of GlcNAc from proteins. Global O-GlcNAcylation and specifically tau O-GlcNAcylation is decreased in AD brain. These observations suggest that decreased brain glucose metabolism may promote abnormal hyperphosphorylation of tau via down-regulation of O-GlcNAcylation, a sensor of intracellular glucose metabolism. However, tau is abnormally hyperphosphorylated at multiple phosphorylation sites and phosphorylation at various sites has different impacts on tau function and pathology. How O-GlcNAcylation affects site-specific tau phosphorylation in vivo is not well understood. In this study, we injected a highly selective OGA inhibitor, thiamet-G, into the lateral ventricle of mice to increase OGlcNAcylation of proteins and investigated alterations of sitespecific tau phosphorylation. We found that acute high-dose thiamet-G treatment led to decreased phosphorylation at some sites but increased phosphorylation at other sites of tau in the brain. We further investigated possible underlying mechanisms for these differential effects.