Repository logo

Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia.

Published version

Change log


Kopach, Olga 
Maiolino, Marta 
Lariccia, Vincenzo 
Amoroso, Salvatore 


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.



4R tau, AMPA receptors, MAPT 10+16, NMDA receptors, calcium signaling, frontotemporal dementia, glutamate, induced pluripotent stem cells, mitochondrial antioxidants, mitochondrial reactive oxygen species, tau, Frontotemporal Dementia, Humans, Induced Pluripotent Stem Cells, Mitochondria, Neurons, Reactive Oxygen Species, Receptors, N-Methyl-D-Aspartate, tau Proteins

Journal Title

Alzheimers Dement

Conference Name

Journal ISSN


Volume Title