As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neuron...As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neurons. Recent studies suggest that tau is also actively involved in regulation of cell viability and enzymatic reaction. In Alzheimer disease (AD) and other tauopathies, tau proteins are abnormally hyperphosphorylated or cleaved, or the gene mutated, which result in intracellular tau accumulation and formation of neurofibrillary tangles in the degenerated neurons. In addition to hyperphosphorylation, many other types of tau posttranslational modifications have been identified in the brains of AD patients and/or the transgenic mouse models. To date, it is not clear how the abnormality of tau causes neurodegeneration and memory deficits. By overexpressing human full-length wildtype tau to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that tau accumulation activated JAK2 to phosphorylate STAT1 at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of NMDAR through direct binding to the specific GAS element of Glu N1, Glu N2A and Glu N2B promoters, while knockdown STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued tau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance.These findings indicate that tau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, which reveals a novel mechanism for tau-associated synapse and memory deficits in AD and other tauopathies.展开更多
In 2002,the Core Committee of the Institute for International Medical Education(IIME)developed the concept of Global Minimum Essential Requirements in Medical Education("essentials"),in which a set of minimu...In 2002,the Core Committee of the Institute for International Medical Education(IIME)developed the concept of Global Minimum Essential Requirements in Medical Education("essentials"),in which a set of minimum outcomes have been defined for the medical students to demonstrate at graduation.To attain these requirements,the Ministry of Education of the People’s Republic of China has proposed the Outstanding Clinician Cultivation Plan in the National Outline of Medium and Long-term Program for Education Reform and Development(2010-2020).Among the proposed seven outcomes in the"essentials",the core competence includes critical thinking and research,communication skills,and information management.To this end,we have taken various measures to maximally implement the Outstanding Clinician Cultivation Plan in pathophysiology teaching.In this meeting,I would like to share with our colleagues the thoughts to reform the functional experimental courses by a substantial interdisciplinary cooperation through Physiology,Pathophysiology and Pharmacology Departments.Based on the preliminary trials,we feel that the reform can ensure the resource sharing(teachers and the laboratory equipments),and also allows us to carry out the experiments gradually from basic skill training,unifactorial and multifactorial/integrative experiments,to the explorative scientific research,which is beneficial not only for the students but also for the young teachers in cultivating their creative thinking,communication skills,and information management.We also believe that getting in touch with the clinical patients in early stage during pathophysiology teaching will nurture the students with right professional values and humanitarian feelings in addition to eliciting the interests of learning.展开更多
Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid...Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid （OA） into the Meynert nucleus basalis of rats and found that 0.4 pmol of OA injeetion induced approximately 60% inhibition of PP2A 24 h after injection, 13% inhibition 48 h after injection and no obvious inhibition 72 h after injection. Hyperphosphorylation of Tau at Ser-198/ Ser-199/Ser-202 and Ser-396/Ser-404 and spatial memory deficit of rats were induced 24 h after 0. d prnol of OA injection. This study suggests that a dowreregulation of PP2A may underlie almormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration in AD.展开更多
文摘As a structural protein, the physiological function of tau proteins is to promote microtu-bule assembly and maintain the stability of the microtubules, so that to build up the tracks for axonal transport of the neurons. Recent studies suggest that tau is also actively involved in regulation of cell viability and enzymatic reaction. In Alzheimer disease (AD) and other tauopathies, tau proteins are abnormally hyperphosphorylated or cleaved, or the gene mutated, which result in intracellular tau accumulation and formation of neurofibrillary tangles in the degenerated neurons. In addition to hyperphosphorylation, many other types of tau posttranslational modifications have been identified in the brains of AD patients and/or the transgenic mouse models. To date, it is not clear how the abnormality of tau causes neurodegeneration and memory deficits. By overexpressing human full-length wildtype tau to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that tau accumulation activated JAK2 to phosphorylate STAT1 at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of NMDAR through direct binding to the specific GAS element of Glu N1, Glu N2A and Glu N2B promoters, while knockdown STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued tau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance.These findings indicate that tau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, which reveals a novel mechanism for tau-associated synapse and memory deficits in AD and other tauopathies.
文摘In 2002,the Core Committee of the Institute for International Medical Education(IIME)developed the concept of Global Minimum Essential Requirements in Medical Education("essentials"),in which a set of minimum outcomes have been defined for the medical students to demonstrate at graduation.To attain these requirements,the Ministry of Education of the People’s Republic of China has proposed the Outstanding Clinician Cultivation Plan in the National Outline of Medium and Long-term Program for Education Reform and Development(2010-2020).Among the proposed seven outcomes in the"essentials",the core competence includes critical thinking and research,communication skills,and information management.To this end,we have taken various measures to maximally implement the Outstanding Clinician Cultivation Plan in pathophysiology teaching.In this meeting,I would like to share with our colleagues the thoughts to reform the functional experimental courses by a substantial interdisciplinary cooperation through Physiology,Pathophysiology and Pharmacology Departments.Based on the preliminary trials,we feel that the reform can ensure the resource sharing(teachers and the laboratory equipments),and also allows us to carry out the experiments gradually from basic skill training,unifactorial and multifactorial/integrative experiments,to the explorative scientific research,which is beneficial not only for the students but also for the young teachers in cultivating their creative thinking,communication skills,and information management.We also believe that getting in touch with the clinical patients in early stage during pathophysiology teaching will nurture the students with right professional values and humanitarian feelings in addition to eliciting the interests of learning.
基金Supported by the National Natural Science Foundation of China(30370560 ,39925012 ,30100057 ,30170221) and a Grant fromthe Li Founda-tion, USA
文摘Hyperphosphorylation of Tau in Alzheimer＇s disease （AD） brain appears to be caused by a down-regulation of protein phospbatase 2A （PP2A）. In this study, we selectively inhibited PP2A by injection of okadaic acid （OA） into the Meynert nucleus basalis of rats and found that 0.4 pmol of OA injeetion induced approximately 60% inhibition of PP2A 24 h after injection, 13% inhibition 48 h after injection and no obvious inhibition 72 h after injection. Hyperphosphorylation of Tau at Ser-198/ Ser-199/Ser-202 and Ser-396/Ser-404 and spatial memory deficit of rats were induced 24 h after 0. d prnol of OA injection. This study suggests that a dowreregulation of PP2A may underlie almormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration in AD.
