Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

Abstract

The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

The Emerging Link between O-GlcNAc and Alzheimer Disease

“…OGA inhibition has been found to decrease the numbers of axonal filopodia (96), enhance long-term potentiation (97), and also to correct breathing defects that occur in Tau.P301L mice (86). These data suggest that OGA inhibition may have beneficial effects in AD that are independent of blocking tau and A␤ toxicity.…”

“…Accordingly, decreased O-GlcNAc may thus contribute to the propagation of toxic species in the brain and enable the spread of these hallmark pathologies within the AD brain. Nevertheless, regardless of the precise mechanisms that are operative, the consistent lack of apparent toxicity of OGA inhibitors (48,78,86,94,95,100), coupled with the clear protective effects of perturbing O-GlcNAc cycling, suggests that OGA inhibitors are a promising potential disease-modifying monotherapy for AD and other tauopathies. Such compounds may represent an opportunity to positively influence the toxicity associated with both tau and A␤ and accordingly alter the course of both hallmark pathologies of AD.…”

“…Using Thiamet-G in the Tau.P301L model, Van Leuven and co-workers (86) found that 2.5 months of treatment decreased the number of neurons showing tau pathology and decreased behavioral defects and weight loss while also increasing survival at 9.5 months. Interestingly, the investigators proposed that, within this model, tau is not O-GlcNAcylated, which varies from observations made by other groups in transgenic tauopathy models and human brain.…”

Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice

“…1a). Because of the potential relevance of O-GlcNAc modification of tau to AD 17,[32][33][34] , the presence of this modification was also assessed by western blot analysis with the site-specific antibody Ab3925 (ref. 35).…”

Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system

“…Because an increase in tau O-GlcNAc levels acts to decrease pathologically relevant phosphorylation at specific sites including Ser396 and Thr231, inhibition of OGlcNAcase activity was expected to block the accumulation of tau aggregates. Indeed, pharmacological inhibition of OGA with thiamet-G in the mice model, decreased tau aggregation, the number of NFTs, and showed marked neuronal loss (Borghgraef et al, 2013;Yuzwa et al, 2012). Thus, O-GlcNAcase inhibition might therefore be a potential therapeutic strategy for attenuating the propagation of tau pathology in Alzheimer's disease and other tauopathies.…”