a Department of Brain and Cognitive Sciences , Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR , Tehran , Iran.
b Division of Translational Therapeutics, Department of Medicine , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.
Hum Vaccin Immunother. 2018 Feb 1;14(2):277-284. doi: 10.1080/21645515.2017.1393594. Epub 2017 Dec 1.
Alzheimer's disease (AD) is a progressive neurological disorder having two major pathological hallmarks: the extracellular senile plaques and intracellular neurofibrillary tangles composed of amyloid beta protein and hyperphosphorylated tau respectively. Removal of protein deposits from AD brains are the newer attempts for treating AD. The major developments in this direction have been the amyloid and tau based therapeutics. While senile plaque removal employing monoclonal antibodies (mAbs) restore brain function in mouse models of AD, tau has been recently introduced as the major neurodegenerative factor mediating neural cell death. So, several research groups have focused on tau therapy. So far, the outcome of tau immunotherapy has been promising and clearance of hyperphosphorylated tau has been shown to restore the brain function in animal models. But the point is which phosphorylated tau is the most critical form to be removed from the brain, especially because removal of physiologic tau can cause neurodegenerative consequence. Recently, we have shown that phosphorylated tau at Thr231 in the cis conformation is a very early driver of neurodegeneration and cis mAb treatment efficiently restores brain structure and function in TBI models. Because of efficient therapeutic effects in mice model of TBI and considering cis pT231-tau accumulation in AD brains, it could be a very good candidate for tau immunotherapy upon several tauopathy disorders including AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，具有两个主要的病理学特征：细胞外老年斑和细胞内神经原纤维缠结，分别由淀粉样β蛋白和过度磷酸化的 tau 组成。从 AD 大脑中清除蛋白质沉积是治疗 AD 的新尝试。这方面的主要进展是基于淀粉样蛋白和 tau 的治疗方法。虽然使用单克隆抗体（mAbs）清除老年斑可以恢复 AD 小鼠模型的大脑功能，但 tau 最近被引入为介导神经细胞死亡的主要神经退行性因素。因此，一些研究小组专注于 tau 治疗。到目前为止，tau 免疫疗法的结果是有希望的，并且已经表明清除过度磷酸化的 tau 可以恢复动物模型中的大脑功能。但问题是，从大脑中清除哪种磷酸化的 tau 是最关键的形式，特别是因为清除生理性 tau 可能会导致神经退行性后果。最近，我们已经表明 cis 构象中 Thr231 位点磷酸化的 tau 是神经退行性变的早期驱动因素，cis mAb 治疗可以有效地恢复 TBI 模型中的大脑结构和功能。由于 cis pT231-tau 在 TBI 小鼠模型中具有有效的治疗效果，并且考虑到 AD 大脑中 cis pT231-tau 的积累，它可能是包括 AD 在内的几种 tau 病的 tau 免疫疗法的一个很好的候选物。
