Distinct Neurotoxic Effects of Extracellular Tau Species in Primary Neuronal-Glial Cultures


Recent data from various experimental models support the link between extracellular tau and neurodegeneration; however, the exact mechanisms by which extracellular tau or its modified forms or aggregates cause neuronal death remain unclear. We have previously shown that exogenously applied monomers and oligomers of the longest tau isoform (2N4R) at micromolar concentrations induced microglial phagocytosis of stressed-but-viable neurons in vitro. In this study, we investigated whether extracellular phosphorylated tau2N4R (p-tau2N4R), isoform 1N4R (tau1N4R) and K18 peptide can induce neuronal death or loss in primary neuronal-glial cell cultures. We found that p-tau2N4R at 30 nM concentration induced loss of viable neurons; however, 700 nM p-tau2N4R caused necrosis of both neurons and microglia, and this neuronal death was partially glial cell-dependent. We also found that extracellular tau1N4R oligomers, but not monomers, at 3 μM concentration caused neuronal death in mixed cell cultures: self-assembly tau1N4R dimers-tetramers induced neuronal necrosis and apoptosis, whereas Aβ-promoted tau1N4R oligomers caused glial cell-dependent loss of neurons without signs of increased cell death. Monomeric and pre-aggregated tau peptide containing 4R repeats (K18) had no effect in mixed cultures, suggesting that tau neurotoxicity might be dependent on N-terminal part of the protein. Taken together, our results show that extracellular p-tau2N4R is the most toxic form among investigated tau species inducing loss of neurons at low nanomolar concentrations and that neurotoxicity of tau1N4R is dependent on its aggregation state.

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Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon request.




1–42 :

Amyloid-β 1 to 42 amino acid peptide


Alzheimer’s disease


Cytosine β- D–arabinofuranoside


Bovine serum albumin


Cerebellar granule cells


Cerebrospinal fluid


Days in vitro


Dulbecco’s Modified Eagle Medium


Glycogen synthase kinase-3β


(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)


Ethylenediaminetetraacetic acid


Extracellular signal-regulated kinases


Interstitial fluid


Microtubule-associated protein tau


Mitogen-activated protein kinases




Neurofibrillary tangles


Paired helical filaments


Propidium iodide


Polyvinylidene fluoride


Tubulin associated unit

tau1N4R :

Recombinant full-length tau 1N4R

tau2N4R :

Recombinant full-length tau 2N4R


Phosphorylated tau

p-tau2N4R :

GSK-3β-phosphorylated recombinant full-length tau 2N4R


Sodium dodecyl sulfate


Sodium dodecyl sulfate–polyacrylamide gel electrophoresis


Lithium dodecyl sulfate


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This work was supported by the Research Council of Lithuania, Bilateral Exchange Project Joint Research grant S-LJB-18-2 INFLAMTAU.

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KP carried out experiments on cell cultures, analysed and wrote the manuscript. LK and VS performed expression and purification of recombinant tau protein. RM planned the experiments, analysed data and wrote the manuscript. TT analysed data and wrote the manuscript. VB initiated, planned and supervised the study, wrote the manuscript. All authors reviewed the final manuscript.

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Correspondence to Katryna Pampuscenko.

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Pampuscenko, K., Morkuniene, R., Krasauskas, L. et al. Distinct Neurotoxic Effects of Extracellular Tau Species in Primary Neuronal-Glial Cultures. Mol Neurobiol 58, 658–667 (2021). https://doi.org/10.1007/s12035-020-02150-7

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  • Tau protein
  • Cell death
  • Microglia
  • Neurons
  • Alzheimer’s disease
  • Tauopathy