Li Xu, Lu Fen, Wang Jian-Zhi, Gong Cheng-Xin
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P.R. China.
Eur J Neurosci. 2006 Apr;23(8):2078-86. doi: 10.1111/j.1460-9568.2006.04735.x.
Impaired brain glucose uptake/metabolism precedes the symptoms of Alzheimer disease (AD) and is likely to play a role in the development of the disease, but the mechanism by which it contributes to AD is not understood. Because glucose uptake/metabolism regulates protein O-GlcNAcylation, and the latter modulates phosphorylation of tau inversely, we investigated, in fasting Kunming mice, whether impaired brain glucose uptake/metabolism causes abnormal hyperphosphorylation of tau and, consequently, facilitates the neurofibrillary degeneration of AD via down-regulation of tau O-GlcNAcylation. We found that fasting caused decreased tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied. The hippocampus was found more vulnerable to the tau alterations than the cerebral cortex, which is consistent with the fact that it is the hippocampus that is first affected in AD. Furthermore, hyperphosphorylation of tau induced by fasting was reversible in the brain after re-feeding. These findings provide a novel mechanism explaining how impaired brain glucose uptake/metabolism contributes to AD and suggest that it may be feasible to treat AD by reversing the abnormal hyperphosphorylation of tau at early stages of the disease.
大脑葡萄糖摄取/代谢受损先于阿尔茨海默病（AD）症状出现，且可能在该疾病的发展中起作用，但目前尚不清楚其导致AD的机制。由于葡萄糖摄取/代谢调节蛋白质O-连接的N-乙酰葡糖胺化（O-GlcNAcylation），而后者又反向调节tau蛋白的磷酸化，因此我们在禁食的昆明小鼠中研究了大脑葡萄糖摄取/代谢受损是否会导致tau蛋白异常过度磷酸化，进而通过下调tau蛋白的O-GlcNAcylation促进AD的神经纤维变性。我们发现，禁食导致tau蛋白的O-GlcNAcylation减少，同时在所研究的大多数磷酸化位点tau蛋白发生过度磷酸化。结果发现，海马体比大脑皮层更容易受到tau蛋白变化的影响，这与AD中首先受影响的是海马体这一事实相符。此外，禁食诱导的tau蛋白过度磷酸化在重新喂食后在大脑中是可逆的。这些发现提供了一种新机制，解释了大脑葡萄糖摄取/代谢受损如何导致AD，并表明在疾病早期通过逆转tau蛋白的异常过度磷酸化来治疗AD可能是可行的。
