Andorfer C A, Davies P
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Dev Neurosci. 2000;22(4):303-9. doi: 10.1159/000017454.
PKA phosphorylations of tau may be an early event in the development of neurofibrillary pathology in Alzheimer's disease. Serines 214 and 409 of tau are highly phosphorylated in PHF-tau, but are not phosphorylated to any significant extent in normal adult human brain; both of these sites are phosphorylated in human fetal tissue. To further study this phenomenon, a developmental characterization of these phosphorylation sites relative to PKA, cAMP-dependent response binding element (CREB) and phosphorylated CREB was performed using samples from mouse brain. Immunoblot analysis using antibodies specific for phospho-serine 214 (CP-3) and phospho-serine 409 (PG-5) revealed a marked decrease in phosphorylation occurring at each of these sites between postnatal day 11 (P11) and P20. Immunoblots with TG-5, a pan-tau antibody, revealed uniform expression of tau during postnatal development, as well as a switch in isoform composition that is evident between P7 and P11. This switch in isoform composition just precedes the change in the extent of phosphorylation at serines 214 and 409, and occurs at a time when PKA phosphorylation of CREB is increasing.
tau蛋白的蛋白激酶A（PKA）磷酸化可能是阿尔茨海默病神经原纤维病理发展过程中的早期事件。在成对螺旋丝（PHF）-tau中，tau蛋白的丝氨酸214和409高度磷酸化，但在正常成人大脑中没有明显的磷酸化；在人类胎儿组织中，这两个位点都发生了磷酸化。为了进一步研究这一现象，利用小鼠脑样本对这些磷酸化位点相对于PKA、环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）和磷酸化CREB进行了发育特征分析。使用针对磷酸化丝氨酸214（CP-3）和磷酸化丝氨酸409（PG-5）的特异性抗体进行免疫印迹分析，结果显示在出生后第11天（P11）至第20天之间，这些位点的磷酸化显著减少。用泛tau抗体TG-5进行的免疫印迹显示，tau蛋白在出生后发育过程中表达均匀，并且在P7和P11之间明显出现了异构体组成的转变。异构体组成的这种转变恰好先于丝氨酸214和409磷酸化程度的变化，并且发生在CREB的PKA磷酸化增加的时候。
