Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada.
J Neurochem. 2010 Sep 1;114(5):1353-67. doi: 10.1111/j.1471-4159.2010.06855.x. Epub 2010 Jun 10.
In tauopathies including Alzheimer's disease, the axonal microtubule-associated protein tau becomes hyperphosphorylated at pathological epitopes and accumulates in the somato-dendritic compartment. However, it remains unclear whether tau becomes phosphorylated at these epitopes in the somato-dendritic compartment and/or in the axon. In primary hippocampal neurons where human tau was over-expressed both in the somato-dendritic compartment and the axon, the pathological epitopes recognized by the antibodies AT8 (S199/S202/T205), AT100 (T212/S214/T217), and AT180 (T231/S235) were found in the somato-dendritic compartment but not in the axon where tau was either not phosphorylated (T205 and T217) or not simultaneously phosphorylated (T231 and S235) at sites included in the above epitopes. When transfected neurons were treated with the phosphatase inhibitor, okadaic acid, AT8, AT100 and AT180 epitopes were observed in the axon, indicating that tau was dephosphorylated at selective sites of pathological epitopes in this compartment. Expression of tau mutants where one phosphorylation site included in the above epitopes was mutated in alanine showed that the formation of one of these epitopes was not required for the formation of the two others in primary hippocampal neurons. All together our results indicate that in the somato-dendritic compartment, the kinase and phosphatase activity does not prevent the formation of pathological epitopes whereas in the axon, the amount of tau phosphorylated at the pathological epitopes is regulated by phosphatase activity, most likely that of phosphoserine/phosphothreonine phosphatase 2A, the major tau phosphatase. This indicates that if the pathological epitopes are initially formed in the axon in Alzheimer's disease brain, the activation of phosphatases could be an efficient way to abolish their generation.
在包括阿尔茨海默病在内的 tau 病中，轴突微管相关蛋白 tau 在病理表位处发生过度磷酸化，并在体树突区积累。然而，tau 是否在体树突区和/或轴突中在这些表位处发生磷酸化仍然不清楚。在原代海马神经元中，人 tau 同时在体树突区和轴突中过表达，被抗体 AT8（S199/S202/T205）、AT100（T212/S214/T217）和 AT180（T231/S235）识别的病理表位在体树突区中被发现，但不在轴突中被发现，在轴突中 tau 要么未被磷酸化（T205 和 T217），要么未同时在上述表位中的位点被磷酸化（T231 和 S235）。当转染神经元用磷酸酶抑制剂 okadaic 酸处理时，在轴突中观察到 AT8、AT100 和 AT180 表位，表明在该区域中 tau 在选择性病理表位处被去磷酸化。在包含上述表位之一的磷酸化位点突变为丙氨酸的 tau 突变体的表达表明，在原代海马神经元中，这些表位之一的形成不需要其他两个表位的形成。总之，我们的结果表明，在体树突区中，激酶和磷酸酶活性不会阻止病理表位的形成，而在轴突中，tau 在病理表位处的磷酸化程度受磷酸酶活性的调节，最有可能是磷酸丝氨酸/磷酸苏氨酸磷酸酶 2A，即主要的 tau 磷酸酶。这表明，如果病理表位最初在阿尔茨海默病大脑中的轴突中形成，那么激活磷酸酶可能是消除其生成的有效方法。
