Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia. Issue 2 (31st May 2021)

• Record Type: Journal Article
• Authors: Esteras, Noemí; Kopach, Olga; Maiolino, Marta; Lariccia, Vincenzo; Amoroso, Salvatore; Qamar, Seema; Wray, Selina; Rusakov, Dmitri A.; Jaganjac, Morana; Abramov, Andrey Y.
• Is Part Of: Alzheimer's & dementia. Volume 18:Issue 2(2022)
• Page Start: 318
• Page End: 338
• Publication Date: 2021-05-31
• Subjects: 4R tau -- AMPA receptors -- calcium signaling -- frontotemporal dementia -- glutamate -- induced pluripotent stem cells -- MAPT 10+16 -- mitochondrial antioxidants -- mitochondrial reactive oxygen species -- NMDA receptors -- tau; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.12394
• Languages: English
• ISSNs: 1552-5260

Abstract

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. Abstract : Tau‐induced mitochondrial reactive oxygen species (ROS) promote α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)/ N‐methyl‐D‐aspartate receptor (NMDAR)‐mediated Ca 2+ ‐excitotoxicity and neuronal death in 4R tauopathies . 10+16 MAPT mutation induces an increase in 4R tau and is causative of frontotemporal dementia. 10+16 MAPT induced pluripotent stem cell (iPSC)‐derived neurons either from patients or genetically engineered, present mitochondrial hyperpolarization resulting in increased mitochondrial ROS production compared to healthy donors or their isogenic wild‐type tau counterpart. Our results indicate that mitochondrial ROS overproduction promotes an increase in the surface levels of specific subunits (NR2B and GluA1) of NMDAR and AMPAR, probably via the oxidation of specific peptides and proteins involved in their trafficking. This leads to the upregulation of glutamate‐induced calcium signaling, resulting in calcium overload and ultimately cell death. Treatment of neurons with the mitochondrial antioxidants MitoQ or MitoTEMPO reduces the surface levels of these NMDAR and AMPAR subunits, avoids the glutamate‐induced calcium overload, and protects against excitotoxicity. Importantly, extracellular 4R tau, either secreted by the iPSC neurons from patients or the recombinant K18 fragment, exert the same calcium deregulation in control neurons, which can also be prevented with mitochondrial antioxidants. These data suggest an additional role for extracellular tau in the spread of the disease and the neuronal dysfunction.