At this point it is at least clearly
At this point, it is at least clearly known that O-GlcNAcylation plays a significant role in AD pathophysiology which makes this post-translational modification an attractive target to tackle this devastating neurodegenerative disease. Using a pharmacological approach to modulate O-GlcNAcylation in differentiated SH-SY5Y cells, this study reveals that Thiamet-G is able to induce a robust augment in global O-GlcNAcylation levels (Fig. 8C and D) without affecting neither cell viability (Fig. 8A) nor ΔΨm (Fig. 8B). Accordingly, Yuzwa and collaborators demonstrated that Thiamet-G increases O-GlcNAcylation levels in PC12 cells and no signs of toxicity were detected . Concerning the protective potential of Thiamet-G, we found that only the pre-treatment with Thiamet- G was able to prevent loss of O-GlcNAcylation levels (Fig. 9) and cell viability (Fig. 10) demonstrating that under our in vitro experimental settings Thiamet-G demonstrated a preventive role. It has been previously demonstrated that Thiamet-G increases O-GlcNAcylation levels in JNPL3 transgenic mice, which express a mutant hyperphosphorylated and aggregate-prone tau isoform, and decreases the extent of NFTs in the brain, slowing down tau-driven neurodegeneration . The same authors also found that increased O-GlcNAcylation decreases the formation of tau Filipin Complex structure in vitro, without changing its structural monomeric form, causing neuronal cell loss [56,57]. In the same line, Hastings and colleagues  reported that chronic inhibition of OGA, through genetic and pharmacological approaches, reduces pathological tau in the brain and total tau in cerebrospinal fluid of rTg4510 mice probably by directly increasing O- GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation. Yuzwa and colleagues also demonstrated that Thiamet-G increases O-GlcNAcylation, attenuates Aβ burden, the formation of neuritic plaques and memory deficits in a mice bearing both mutated human tau and APP (TAPP mice) . Another OGA inhibitor, 1,2-dideoxy-2′-propyl-α-d-glucopyranoso-[2,1-D]-Δ2′-thiazoline (NButGT), caused a reduction of Aβ production by lowering γ-secretase activity both in vitro and in vivo . Moreover, NButGT attenuated the accumulation of Aβ, neuroinflammation, and memory impairment in the 5XFAD mice .
Conclusion Our results support the idea that reduced O-GlcNAcylation underlies AD pathology representing a “sweet” route to tackle this devastating neurodegenerative disease. However, further studies are required to clarify the key mechanisms associated to the loss O-GlcNAcylation that contribute to the onset and/or aggravation of AD pathology.
Acknowledgements Sónia C. Correia has a post-doctoral fellowship (SFRH/BPD/109822/2015) from the Fundação para a Ciência e a Tecnologia (FCT). Tiffany S. Pinho is recipient of a research fellowship from the Healthy Aging 2020 (CENTRO-01-0145-FEDER-000012). The authors' work is supported by FEDER funds through the Operational Programme Competitiveness Factors — COMPETE, national funds by FCT under the project PEst-C/SAU/LA0001/2013-2014 and strategic project UID/NEU/04539/2013 and Santa Casa da Misericórdia de Lisboa - Mantero Belard Award 2015 (MB-1049-2015).
Introduction Mitochondria are one of the major targets for development of effective treatment strategies in both acute brain injury and neurodegenerative diseases. They are essential in the maintenance of normal cellular functions, mainly through regulation of energy production [, , , , ]. The cells' energy demand is affecting not only the activity of mitochondrial oxidative phosphorylation but also the mitochondrial structure and movement. Mitochondria respond to energetic stress by re-organizing their sub-cellular distribution and also by structural and morphological alterations [4,, , ]. This unique ability of mitochondria to spatially and morphologically adapt to changing intracellular environments is termed “mitochondrial dynamics”.