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).T...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 Ba-subunit-contalning protein phosphatase 2A(PP2A-Ba),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.展开更多
基金This work was supported in parts by the National Key R&D Program of China(2016YFC1305800,to J-Z.W.)the Special project of technological innovation of Hubei Province(2018ACA142,to J-Z.W.)+4 种基金the Natural Science Foundation of China(31730035,81721005,91949205,to J-Z.W.81901107,to J.Z.)the China Postdoctoral Science Foundation(2018M632872,to J.Z.)the Guangdong Provincial Key S&T Program(2018B030336001,to J-Z.W)the Science and Technology Program of Guizhou Province(Qiankehe zhicheng[2021]yiban 423,to J.Z.).We thank prof.Keqiang Ye for the generous gifts of hTau-N368 plasmid and the antibody,prof.Xiongwei Zhu for the help in electron microscopy,and all members in Wang-lab for helpful discussion and suggestions.
文摘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 Ba-subunit-contalning protein phosphatase 2A(PP2A-Ba),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.
