Gong Cheng-Xin, Liu Fei, Grundke-Iqbal Inge, Iqbal Khalid
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.
J Alzheimers Dis. 2006 Mar;9(1):1-12. doi: 10.3233/jad-2006-9101.
Neurofibrillary degeneration characterized by abnormal hyperphosphorylation and aggregation of tau in affected neurons is directly associated with dementia symptoms and plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and related tauopathies. It is well established that brain glucose uptake/metabolism is impaired in AD, but how this impairment contributes to the disease is unknown. We recently found that tau in human brain is also modified by O-GlcNAcylation in addition to phosphorylation and that the former negatively regulates the latter. On the basis of these findings, we propose a novel hypothesis that the impaired glucose uptake/metabolism contributes to AD by facilitating abnormal hyperphosphorylation of tau. Further studies of this mechanism are likely to offer a novel therapeutic target for preventing and treating AD.
以受影响神经元中tau蛋白异常过度磷酸化和聚集为特征的神经原纤维变性与痴呆症状直接相关，并且在阿尔茨海默病（AD）及相关tau蛋白病的发病机制中起关键作用。众所周知，AD患者脑葡萄糖摄取/代谢受损，但这种损伤如何导致疾病尚不清楚。我们最近发现，人脑中的tau蛋白除了发生磷酸化外，还会发生O-连接N-乙酰葡糖胺化修饰，并且前者对后者起负调控作用。基于这些发现，我们提出了一个新的假说，即受损的葡萄糖摄取/代谢通过促进tau蛋白的异常过度磷酸化而导致AD。对这一机制的进一步研究可能会为预防和治疗AD提供一个新的治疗靶点。
