Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promisin...Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.展开更多
Dear Editor,COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the seventh coronavirus known to infect humans.The COVID-19 pandemic has spread to more than 200countries,with...Dear Editor,COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the seventh coronavirus known to infect humans.The COVID-19 pandemic has spread to more than 200countries,with more than 600 million confirmed cases and over 6.5million deaths as of September 2022,posing a huge challenge to global public health.展开更多
基金supported by the National Natural Science Foundation of China(82230041,91949205,31730035,81721005)the National Key R&D Program of China(2016YFC1305800)the Guangdong Provincial Key S&T Program(018B030336001)。
文摘Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.
基金supported by the STS regional key project(KFJSTSQYZD-2021-12-001 to Z.M.Y.and C.S.)from the Chinese Academy of Sciencesthe National Key R&D Program of China(2021YFC0863300 to Z.M.Y.and C.S.)+1 种基金the Emergency Novel Coronavirus Pneumonia Project from the Ministry of Science and Technology of China(2020YFC0844700)Huazhong University of Science and Technology(2020KFYXGYJ098)
文摘Dear Editor,COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is the seventh coronavirus known to infect humans.The COVID-19 pandemic has spread to more than 200countries,with more than 600 million confirmed cases and over 6.5million deaths as of September 2022,posing a huge challenge to global public health.
