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Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia
Author(s) -
Esteras Noemí,
Kopach Olga,
Maiolino Marta,
Lariccia Vincenzo,
Amoroso Salvatore,
Qamar Seema,
Wray Selina,
Rusakov Dmitri A.,
Jaganjac Morana,
Abramov Andrey Y.
Publication year - 2022
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12394
Subject(s) - excitotoxicity , glutamate receptor , microbiology and biotechnology , neuroscience , glutamatergic , biology , ampa receptor , mitochondrion , chemistry , receptor , biochemistry
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.