Abstract
Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation.
Highlights
Hyperphosphorylated tau is the major component of neurofibrillary tangles (NFTs) in Alzheimer disease (AD)
The results showed that synaptic N-methyl-D aspartate receptor (NMDAR) activation for 12 and 24 h did not change total (R134d) and phosphorylated tau levels, except that Tau-1-recognized
Extrasynaptic NMDAR activation causes neuronal death and neurodegeneration,[9,10,11] which is suggested to be involved in AD pathogenesis
Summary
Hyperphosphorylated tau is the major component of neurofibrillary tangles (NFTs) in Alzheimer disease (AD). Physiological activation of NMDAR plays key roles in multiple neurological functions such as synaptic plasticity, neuronal development and survival, learning and memory.[7] On the contrary, excessive NMDAR activation is toxic to neurons. Activation of synaptic NMDAR is suggested to improve synaptic plasticity and learning and memory ability, promote neuronal survive and maturation; while activation of extrasynaptic NMDAR (E-NMDAR) could induce neuronal death, synaptic plasticity failure and memory loss,[8] contribute to phenotype onset in Huntington's disease, stroke and AD.[9,10,11] The downstream signaling pathways leading to neuronal survival by synaptic NMDAR and neuronal death by E-NMDAR are widely investigated. Received 25.2.16; revised 12.9.16; accepted 13.9.16; Edited by A Yaron has a key role in cell survival.[8,12] Leveille et al.[12] reported that selective synaptic NMDAR activation induced ERK activation, whereas E-NMDAR activation could not, indicating that E-NMDAR activation shuts off ERK signaling pathway. The underlying mechanism for ERK signaling shutting off by E-NMDARs remains unclarified
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