Abstract
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. 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. 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. These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.
Highlights
The second most common form of early-onset dementia— frontotemporal dementia (FTD)—is often characterized by the aggregation of the microtubule-associated protein tau
Interpretation: Our findings demonstrate that tau impairs glutamatergic signaling via mitochondrial reactive oxygen species (ROS) overproduction, leading to the overactivation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, which results in excessive calcium entry to the cytosol and neuronal death
We report a direct link among mitochondrial ROS, calcium signaling, and glutamatergic transmission deregulation, which might lead to early dysfunction preceding neuronal loss in tauopathies, and, according to our results, is involved in the mechanism of neurodegeneration
Summary
The second most common form of early-onset dementia— frontotemporal dementia (FTD)—is often characterized by the aggregation of the microtubule-associated protein tau. We studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. Results: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Mutations in the MAPT gene, encoding the microtubule-associated protein tau, are known to cause familial frontotemporal dementia (FTD), the second most common cause of early onset dementia.[1] Among them, the intronic 10+16 mutation causes augmented splicing in of MAPT exon 10 and an increase in the proportion of 4R-tau isoforms (containing four repeats of the microtubule-binding domain) versus 3R isoforms (containing three repeats), which are otherwise balanced in the adult brain.
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