摘要
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.
As a structural protein, the physiological function of tau proteins is to promote microtubule 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 N2 A and Glu N2 B promoters, while knockdown STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701 F-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.
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2019年第6期401-402,共2页
Chinese Journal of Pharmacology and Toxicology
