Pei J J, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn R F
Karolinska Institute, NEUROTEC, Section for Geriatric Medicine, Huddinge, Sweden.
J Neuropathol Exp Neurol. 1999 Sep;58(9):1010-9. doi: 10.1097/00005072-199909000-00011.
Accumulation of paired helical filaments (PHFs) in neurofibrillary tangles, neuropil threads, and dystrophic neurites is one of the major neuropathological hallmarks of Alzheimer disease (AD). The principal protein subunit of PHFs is the abnormally hyperphosphorylated tau. Glycogen synthase kinase 3beta (GSK-3beta) is one of the candidate kinases involved in PHF-tau formation. To play a role in PHF-tau formation, it would be expected that GSK-3beta is active in tangle bearing neurons. In the present study, we investigated the regional and intracellular distributions of active and inactive forms of GSK-3beta in brains staged for neurofibrillary changes. We found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3beta appear initially in the Pre-alpha layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes. Active, but not inactive, GSK-3beta was found to initially accumulate in the cytoplasm of pretangle neurons. These data provide direct in situ evidence that is consistent with the involvement of GSK-3beta in PHF-tau formation.
成对螺旋丝（PHF）在神经原纤维缠结、神经毡丝和营养不良性神经突中的积累是阿尔茨海默病（AD）主要的神经病理学特征之一。PHF的主要蛋白质亚基是异常过度磷酸化的tau蛋白。糖原合酶激酶3β（GSK-3β）是参与PHF-tau形成的候选激酶之一。若要在PHF-tau形成中发挥作用，可以预期GSK-3β在含有缠结的神经元中是活跃的。在本研究中，我们调查了在神经原纤维变化分期的大脑中，GSK-3β活性形式和非活性形式的区域及细胞内分布。我们发现，具有活性GSK-3β（而非非活性GSK-3β）阳性的缠结样包涵体的神经元最初出现在内嗅皮质的前α层，并延伸至其他脑区，这与神经原纤维变化的发展顺序一致。活性GSK-3β（而非非活性GSK-3β）最初被发现积聚在缠结前神经元的细胞质中。这些数据提供了直接的原位证据，支持GSK-3β参与PHF-tau形成。
