Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia

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.

Short Overview of Some Assays for the Measurement of Antioxidant Activity of Natural Products and Their Relevance in Dermatology

“…Similarly, redox proteomics is rapidly emerging in oxidative stress research as it can identify Spin traps and spin probes used for electron-spin resonance assays have high selectivity and specificity and are among the essential tools in oxidative stress research. Similarly, redox proteomics is rapidly emerging in oxidative stress research as it can identify ROS targets and modifications induced [49][50][51]. However, low throughput and expensive instruments requiring a high level of expertise reduce their applicability.…”

Human Induced Pluripotent Stem Cell Models of Frontotemporal Dementia With Tau Pathology

“…Additional studies demonstrated altered mitochondrial function in iPSC-derived neurons from patients with the 10 + 16 mutation (Esteras et al, 2017(Esteras et al, , 2021. 10 + 16 neurons carried an increased mitochondrial membrane potential leading to overproduction of cytosolic and mitochondrial reactive oxygen species (ROS).…”

“…10 + 16 neurons exhibited a depolarized AP threshold, a reduced amplitude and altered shape of the induced AP spike and the need for an almost two-fold stronger current that was needed to trigger neurons to fire an AP ( Kopach et al, 2020 ). Furthermore, 10 + 16 patient-derived cortical neurons showed increased expression of AMPA and NMDA receptors containing GluA1 and NR2B subunits leading to altered glutamatergic signaling, calcium overload and excitotoxicity ( Esteras et al, 2021 ). The application of mitochondrial antioxidants MitoQ and MitoTEMPO to the cell culture media led to recovery of impaired Ca ++ signaling and to prevention of cell death ( Esteras et al, 2021 ) as described for MitoQ before ( Esteras et al, 2017 ).…”

“…Furthermore, 10 + 16 patient-derived cortical neurons showed increased expression of AMPA and NMDA receptors containing GluA1 and NR2B subunits leading to altered glutamatergic signaling, calcium overload and excitotoxicity ( Esteras et al, 2021 ). The application of mitochondrial antioxidants MitoQ and MitoTEMPO to the cell culture media led to recovery of impaired Ca ++ signaling and to prevention of cell death ( Esteras et al, 2021 ) as described for MitoQ before ( Esteras et al, 2017 ).…”

“…Further maturation over time results in the formation of first the 0N4R isoform with expression of all six isoforms in human iPSC-derived neurons after 150 days ( Iovino et al, 2015 ) and 365 days ( Sposito et al, 2015 ), respectively, of maturation in vitro . In addition, it was shown that tau protein is also secreted into the medium supernatant of human iPSC-derived neurons ( Esteras et al, 2021 ). These findings highlight that human iPSCs are suitable for modeling FTLD-tau with the caveat that prolonged time windows of differentiation might be necessary to capture certain disease phenotypes in patient-derived neurons.…”