Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture

Topic: Disease mechanisms in lab and animal studies

Background 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. Methods 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. Results We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca 2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca 2+ 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 Ca 2+ 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. Conclusions 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 Ca 2+ influx.

Key findings

• Methods 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.
• Results We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca 2+ influx and neurotoxicity in neurons from wildtype mice.
• Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca 2+ influx.

New to this subject? Start with our plain-English guide: Treatments →

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s13024-017-0176-x
• PubMed: 28526038
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

@article{miyamoto2017-28526038,
  author  = {Miyamoto, T. and Stein, L. and Thomas, R. and Djukic, B. and Taneja, P. and Knox, J. and Vossel, K. and Mucke, L.},
  title   = {{Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture}},
  journal = {Molecular neurodegeneration},
  year    = {2017},
  doi     = {10.1186/s13024-017-0176-x},
  pmid    = {28526038},
  url     = {https://doi.org/10.1186/s13024-017-0176-x}
}

Related studies in Drug development

• Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles The American journal of pathology · 2007-05-01 · usefulness score 36/100
• Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes Scientific reports · 2019-03-15 · usefulness score 41/100
• Tau passive immunization inhibits not only tau but also Aβ pathology Alzheimer's research & therapy · 2017-01-10 · usefulness score 41/100
• Recognition of the minimal epitope of monoclonal antibody Tau-1 depends upon the presence of a phosphate group but not its location Journal of neuroscience research · 1993-02-01 · usefulness score 36/100
• Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein FEBS letters · 1996-04-01 · usefulness score 36/100
• Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope Journal of neurochemistry · 2006-10-01 · usefulness score 36/100

Also tagged “phosphorylation”

387 studies in the library carry the topic tag “phosphorylation”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 387 tagged studies.

• Emerging amyloid and tau targeting treatments for Alzheimer's disease Expert review of neurotherapeutics · 2017-05-19 · usefulness score 39/100 · Drug development
• Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons FEBS letters · 1997-07-01 · usefulness score 36/100 · Drug development
• Tau immunotherapy for Alzheimer's disease Trends in molecular medicine · 2015-04-03 · usefulness score 36/100 · Drug development

Similar studies

• Antisense reduction of tau in adult mice protects against seizures 2013 · Drug development
• Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease 2011 · Risk genes beyond APOE
• Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation 2026 · Disease mechanisms
• Roles of tau protein in health and disease 2017 · Disease mechanisms
• The role of pathological tau in synaptic dysfunction in Alzheimer's diseases 2021 · Disease mechanisms
• Tau at the Crossroads between Neurotoxicity and Neuroprotection 2017 · Drug development

More on Drug development

• A review that covers this ground Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies Expert opinion on investigational drugs · 2023-07-10 · usefulness score 41/100
• Newest in this subject The metabolic-brain axis: GLP-1 signaling, insulin resistance, and obesity pharmacotherapy in neurodegeneration Metabolism: clinical and experimental · 2026-10-30 · Peer-reviewed · usefulness score 45/100
• Newest in this subject Effect of Metformin on tau pathology and proteostasis in cellular and a Drosophila model of Tauopathy Research Square · 2026-10-29 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Drug development →