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Tau accumulation triggers STAT 1‐dependent memory deficits by suppressing NMDA receptor expression
Author(s) -
Li XiaoGuang,
Hong XiaoYue,
Wang Yali,
Zhang ShuJuan,
Zhang JunFei,
Li XiaChun,
Liu YanChao,
Sun DongShen,
Feng Qiong,
Ye JinWang,
Gao Yuan,
Ke Dan,
Wang Qun,
Li Honglian,
Ye Keqiang,
Liu GongPing,
Wang JianZhi
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201847202
Subject(s) - nmda receptor , microbiology and biotechnology , stat , receptor , chemistry , biology , signal transduction , biochemistry , stat3
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 hT au) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hT au accumulation activates JAK 2 to phosphorylate STAT 1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT 1 dimerization, nuclear translocation, and its activation. STAT 1 activation suppresses expression of N‐methyl‐D‐aspartate receptors ( NMDAR s) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT 1 by AAV ‐Cre in STAT 1 flox/flox mice or expressing dominant negative Y701F‐ STAT 1 efficiently rescues hT au‐induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hT au accumulation impairs synaptic plasticity through JAK 2/ STAT 1‐induced suppression of NMDAR expression, revealing a novel mechanism for hT au‐associated synapse and memory deficits.