Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Abstract

Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…Although the mechanisms underlying the above observations remain unclear, it may be explained in part by the observations of Lim and Chang who demonstrated that increased levels of O-GlcNAc are associated with a more soluble pool of Sp1 during thermal stress (Lim and Chang 2006). This may represent altered localization of Sp1, or that Sp1 exhibits increased thermal stability when it is O-GlcNAc-modified (Lim and Chang 2006) similar to Tau (Yuzwa et al 2012). Together, the data discussed above suggest that O-GlcNAc can regulate the expression of HSPs by regulating both HSF-1 and Sp1.…”

“…Recent data have demonstrated that inhibition of O-GlcNAcase, which leads to an increase in OGlcNAc levels, in a murine model of AD led to increased OGlcNAcylation of tau, decreased tau aggregation, and diminished neuronal cell death. Together, these data highlight the protective role of O-GlcNAc and suggest that OGlcNAcase could be a therapeutic target for slowing AD progression (Yuzwa et al 2012). Interestingly, low glucose uptake and metabolism during aging has been postulated to lead to decreased O-GlcNAcylation of key proteins such as Tau, potentially exacerbating the AD phenotype during aging (Yuzwa et al 2012).…”

“…Together, these data highlight the protective role of O-GlcNAc and suggest that OGlcNAcase could be a therapeutic target for slowing AD progression (Yuzwa et al 2012). Interestingly, low glucose uptake and metabolism during aging has been postulated to lead to decreased O-GlcNAcylation of key proteins such as Tau, potentially exacerbating the AD phenotype during aging (Yuzwa et al 2012). …”

“…Some examples include: (1) increased protein solubility during heat stress Lim and Chang 2006) or Alzheimer's disease (Yuzwa et al 2012); (2) reduced calcium overload (Liu et al 2006(Liu et al , 2007; (3) decreased calpain activation (Liu et al 2007); (4) altered p38 MAPK activation in response to ischemia reperfusion injury (Fulop et al 2007b;; (5) modulation of proinflammatory cytokines (Huang et al 2007;Zou et al 2009); (6) reduced mitochondrial permeability transition pore (mPTP) formation ); (7) increased B-cell lymphoma 2 (Bcl-2) expression and translocation (Champattanachai et al 2008); and (8) regulation of the expression of a subset of molecular chaperones (Zachara et al 2004b;Kazemi et al 2010;Sohn et al 2004).…”

Tau-induced neurodegeneration: mechanisms and targets

“…They postulated that tau pathology and neurodegeneration can be caused by impaired brain glucose metabolism via the down-regulation of tau O-GlcNAcylation in AD. Furthermore, O-GlcNAcylation may also inhibit tau oligomerization directly [72] . Therefore, decreased O-GlcNAcylation may promote tau-mediated neurodegeneration by promoting tau oligomerization directly and also indirectly by inducing its abnormal hyperphosphorylation [73] .…”