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Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia

Esteras, Noemi; Kopach, Olga; Maiolino, Marta; Lariccia, Vincenzo; Amoroso, Salvatore; Qamar, Seema; Wray, Selina; Rusakov, Dmitri A.; Jaganjac, Morana; Abramov, Andrey Y. (2022) Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia. Alzheimer's & Dementia, 18 (2). pp. 318-338. ISSN 1552-5260

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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.

Item Type: Article
Uncontrolled Keywords: 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
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Human Genetics, Genomics and Proteomics
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Neuroscience
Divisions: Division of Molecular Medicine
Depositing User: Morana Jaganjac
Date Deposited: 15 Feb 2024 12:30
DOI: 10.1002/alz.12394

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