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

EMBO Rep. 2019 Jun;20(6):e47202. doi: 10.15252/embr.201847202. Epub 2019 May 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Animals
  • Disease Models, Animal
  • Disease Susceptibility
  • Gene Expression Regulation*
  • Humans
  • Janus Kinase 2 / metabolism
  • Memory Disorders / genetics*
  • Memory Disorders / metabolism*
  • Memory Disorders / psychology
  • Mice
  • Models, Biological
  • Neuronal Plasticity
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Receptors, N-Methyl-D-Aspartate
  • STAT1 Transcription Factor
  • tau Proteins
  • Janus Kinase 2