2. Academic Validation
  3. Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression

Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression

  • EMBO Rep. 2019 Jun;20(6):e47202. doi: 10.15252/embr.201847202.
Xiao-Guang Li 1 2,  Xiao-Yue Hong 1,  Ya-Li Wang 1 3,  Shu-Juan Zhang 1,  Jun-Fei Zhang 1,  Xia-Chun Li 1,  Yan-Chao Liu 1,  Dong-Shen Sun 1,  Qiong Feng 1,  Jin-Wang Ye 1,  Yuan Gao 1,  Dan Ke 1,  Qun Wang 1,  Hong-Lian Li 1,  Keqiang Ye 4,  Gong-Ping Liu 5 6,  Jian-Zhi Wang 5 6
Affiliations

Affiliations

  • 1 Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Key Laboratory for the Brain Research of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, China.
  • 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  • 5 Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China liugp111@mail.hust.edu.cn wangjz@mail.hust.edu.cn.
  • 6 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
PMID: 31085626 DOI: 10.15252/embr.201847202
Abstract

Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

Keywords

N‐methyl‐D‐aspartate receptors; STAT1; Tau; memory; synapse.

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