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

ABSTRACT: Intracellular tau accumulation forming neurofibrillary tangles is one hallmark of Alzheimer's disease (AD), but how tau accumulation induces synaptic impairment remains elusive. Here, by overexpressing human full-length wildtype tau (hTau) to mimic tau abnormalities as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2-dependent STAT1 phosphorylation at Tyr701, triggering STAT1 dimerization, activation and nuclear translocation. STAT1 activation subsequently suppresses the expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to specific GAS elements in the GluN1, GluN2A and GluN2B promoters. Knockdown of STAT1, or the expression of dominant negative Y701F-STAT1 in mice, efficiently rescues hTau-induced suppression of NMDAR expression, ameliorating 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 explaining hTau-associated synapse and memory deficits.

SUBMITTER: Dr. Xiaoguang Li

PROVIDER: S-SCDT-EMBOR-2018-47202V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear.We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau.We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt -/-) neurons. Reconstituting tau expression in Mapt -/- neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B-containing NMDA receptors, and do not require binding of Fyn to tau's major interacting PxxP motif or of tau to microtubules.Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx.

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

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