From the CONACYT National Council for Science and Technology, 03940 México, México,
UNAM Developmental Neurobiology and Neurophysiology, Institute of Neurobiology, National Autonomous University of México, 76230 Querétaro, México.
J Biol Chem. 2018 Jun 1;293(22):8462-8472. doi: 10.1074/jbc.RA117.001187. Epub 2018 Apr 9.
Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.
tau 蛋白在几个位点的过度磷酸化，包括靠近微管结构域区域（MDr）的位点，被认为是阿尔茨海默病（AD）发展的关键病理事件。最近的研究表明，在这种疾病的早期阶段，tau 蛋白 MDr 结构域的磷酸化增加与神经元兴奋性的降低有关。从机制上讲，我们发现 1 个月大的三转基因 AD 小鼠中的锥体神经元和一些 parvalbumin 阳性中间神经元积累了过度磷酸化的 tau 蛋白，并且这种积累与海马神经元中 theta 振荡的变化相关。来自年轻三转基因 AD 小鼠的锥体神经元在亚阈膜振荡中表现出较少的尖峰适应和功率增加。此外，与用 4-氨基吡啶处理的对照小鼠相比，用钾通道阻滞剂 4-氨基吡啶处理的三转基因 AD 小鼠的 theta 振幅降低，并且与这些对照不同，在受到这种挑战后没有出现类似癫痫发作的活动。总的来说，我们的结果提供了对 AD 发病机制的新见解，并表明在疾病的初始阶段 tau 磷酸化的增加代表了补偿大脑电路过度兴奋的神经元反应。
