加拿大研究人員研究發(fā)現(xiàn)使用一種酶抑制劑可阻止tau蛋白中糖類的去除,，或可有利于老年癡呆癥的治療,。這項(xiàng)發(fā)現(xiàn)為我們對(duì)老年癡呆癥的內(nèi)在研究提供了新見解,。該研究發(fā)表于本月出版的《自然—化學(xué)生物學(xué)》上,。
老年癡呆癥的癥狀表現(xiàn)為失憶和精神錯(cuò)亂,。從細(xì)胞層面上來看,，該病的特點(diǎn)則是tau蛋白不斷累積,，直至形成較大纖維,。許多研究老年癡呆癥的科學(xué)家往往試圖找到能直接與這些纖維進(jìn)行反應(yīng)的分子，分解或者阻礙纖維的形成,，從而治療此病,。不過，目前還不清楚是什么物質(zhì)控制著這些纖維的形成,；一旦找到纖維的前期形成因素,，那么，老年癡呆癥防治的早期干預(yù)將成為可能,。
David Vocadlo和同事將糖基轉(zhuǎn)移酶（OGT）的抑制劑Thiamet-G注入患有老年癡呆癥的轉(zhuǎn)基因小鼠體內(nèi)后,，發(fā)現(xiàn)tau蛋白累積速度減慢，神經(jīng)細(xì)胞缺失開始減少,。特別是抑制劑成功阻止了酶將tau蛋白中的糖類去除,；實(shí)驗(yàn)檢測也證明這些糖類能直接減慢纖維的形成。（生物谷 bioon.com）
doi:10.1038/nchembio.797
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Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation
Scott A Yuzwa, Xiaoyang Shan, Matthew S Macauley, Thomas Clark, Yuliya Skorobogatko, Keith Vosseller,，David J Vocadlo
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.
