Noemí Esteras1, Olga Kopach2, Marta Maiolino3, Vincenzo Lariccia3, Salvatore Amoroso3, Seema Qamar4, Selina Wray5, Dmitri A Rusakov2, Morana Jaganjac6,7, Andrey Y Abramov1. 1. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. 2. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. 3. Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche,", Ancona, Italy. 4. Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. 5. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. 6. Qatar Analytics & BioResearch Lab, Anti-Doping Lab Qatar, Doha, Qatar. 7. Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
Abstract
INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.
INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.
Authors: Artyom Y Baev; Andrey Y Vinokurov; Irina N Novikova; Viktor V Dremin; Elena V Potapova; Andrey Y Abramov Journal: Cells Date: 2022-02-17 Impact factor: 6.600
Authors: Mitzi M Gonzales; Valentina R Garbarino; Erin Pollet; Juan P Palavicini; Dean L Kellogg; Ellen Kraig; Miranda E Orr Journal: J Clin Invest Date: 2022-05-16 Impact factor: 19.456