Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
Tau is a microtubule-associated protein, found at high levels in neurons, and the aggregation of which is associated with neurodegeneration. Insoluble intracellular aggregates of the tau characterize a number of neurodegenerative diseases collectively termed tauopathies. Recent data indicate that tau can be actively secreted from neurons, but the effects of extracellular tau on neuronal viability still are not clear. We have investigated whether various extracellular tau isoforms – tau 2N4R, phosphorylated tau 2N4R, isoform 1N4R, and tau peptide containing 4R repeats (K18) – at different oligomerisation state can cause neurotoxicity in primary neuronal-glial cell cultures. Recombinant full length tau 2N4R induced primary phagocytosis of stressed neurons by activated microglia. Extracellular phosphorylated tau 2N4R was the most toxic form among investigated tau species inducing loss of neurons at low nanomolar concentrations. Extracellular tau 1N4R caused neuronal death in neuronal-glial cell cultures and the toxicity mechanism was dependent on the oligomerisation state. K18 peptide had no effect in cultures. In summary, our results indicate that neurotoxicity of extracellular tau depends on the isoform as well as on phosphorylation and aggregation state of tau species and involve participation of glial cells. The identification of the link between extracellular tau protein type/state, neuronal dysfunction and glial cell activation status may have potential implications for control of inflammation in neurodegeneration.
This work was supported by the Research Council of Lithuania, Bilateral Exchange Project Joint Research grant S-LJB-18-2 INFLAMTAU.
MORE ABOUT THE SCIENTIST
Professor Ramune Morkuniene graduated from the Faculty of Pharmacy, Kaunas Medical Academy obtaining her PhD in 2000 in Kaunas University of Medicine. She is now senior researcher of Neuroscience Institute, professor of Department of Drug Chemistry and Dean of Faculty of Pharmacy of Lithuanian University of Health Sciences. Her scientific activity fields are investigation of the mechanisms of cell death as well as search of potential protective compounds during neurodegenerative and ischemia/reperfusion pathologies, investigation of the role of cellular energy metabolism in the apoptotic and necrotic processes during various pathologies. R. Morkuniene is Member of Commission for Compensation of Diseases, Medicines and Measures of Medical aid, Ministry of Health of the Republic of Lithuania and Member of Research Council of the State Medicines Control Agency at the Ministry of Health of the Republic of Lithuania. She was supported by Bilateral Exchange Project Joint Research Grant S-LJB-18-2 INFLAMTAU of the Research Council of Lithuania (2018-2020), collaborating with professor Taisuke Tomita of University of Tokyo.