期刊
ALZHEIMERS & DEMENTIA
卷 18, 期 2, 页码 318-338出版社
WILEY
DOI: 10.1002/alz.12394
关键词
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
资金
- Wellcome Trust
- UK Research and Innovation Engineering and Physical Sciences Research Council (EPSRC)
- NIHR Queen Square Biomedical Research Centre
- Alzheimer's Research UK Senior Research Fellowship [ARUK-SRF2016B-2]
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) [2017YH3SXK]
The study found that overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits, leading to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants can restore the altered response and prevent neuronal death. Additionally, extracellular 4R tau induces the same pathological response in healthy neurons, proposing a mechanism for disease propagation.
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 alpha-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.
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