Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacology, Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China.
Signal Transduct Target Ther. 2021 Jul 14;6(1):269. doi: 10.1038/s41392-021-00669-2.
Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.
神经元内过度磷酸化 tau 的积累是二十多种神经退行性疾病的标志性病理学特征，这些疾病统称为 tau 病，包括最常见的阿尔茨海默病 (AD)。因此，选择性去除或减少过度磷酸化的 tau 有望成为 AD 和其他 tau 病的治疗方法。在这里，我们设计并合成了一种新型的去磷酸化靶向嵌合体 (DEPTAC)，以特异性促进 tau 与脑内最活跃的 tau 磷酸酶 Bα 亚基包含的蛋白磷酸酶 2A (PP2A-Bα) 的结合。DEPTAC 表现出在多个 AD 相关位点高效去磷酸化 tau 和在体外和体内防止 tau 积累的能力。进一步的研究表明，DEPTAC 显著改善了转染诱导过表达截断的和神经毒性人 tau N368 的转基因小鼠的微管组装、神经突可塑性以及海马依赖的学习和记忆。我们的数据为选择性去除过度磷酸化的 tau 提供了一种策略，为 AD 及相关 tau 病的靶向治疗开辟了新的思路。
