TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2 2′,4,4′-tetrabromodiphenyl ether (BDE-47)-treated mice

- Adult exposure to BDE-47 is associated with hippocampal apoptosis and cognitive decline in mice.
- BDE-47 treatment induces an increase of nuclear TDP-43 in mouse hippocampus.
- Upregulation of nuclear TDP-43 aggravates hippocampal apoptosis and cognitive deficits in BDE-47-treated mice.
- NLRP3 inflammasome is implicated in TDP-43 pathology via downregulation of Parkin in the hippocampus of BDE-47-treated.

It is now commonly known that exposure to polybrominated diphenyl ethers (PBDEs) may cause neurotoxicity and cognitive deficits in children as well as adults, but the underlying mechanisms are still not clear. In the present study, we aimed to elucidate the potential underlying mechanism of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity and cognitive impairment. Our results showed that BDE-47-treated mice exhibited impaired cognition and robust upregulation of nuclear TDP-43 in the hippocampus. Hippocampus-specific TDP-43 knockdown attenuated hippocampal apoptosis, restored synaptic protein levels and thus improved cognitive dysfunction in BDE-47-treated mice. Furthermore, our data demonstrated that NLRP3 inflammasome activation played a distinct role in the upregulation of nuclear TDP-43 by downregulating Parkin in the hippocampus of BDE-47-treated mice. Knocking down NLRP3 in the hippocampus or inhibiting caspase 1 activity in BDE-47-treated mice effectively increased Parkin expression in the hippocampus, which decreased the levels of nuclear TDP-43 and ultimately abrogated TDP-43-induced neurotoxic effects. Taken together, our data indicate that TDP-43 upregulation mediated by NLRP3 inflammasome activation via Parkin downregulation in the hippocampus induces cognitive decline in BDE-47-treated mice, and suggest that inhibition of NLRP3 or TDP-43 may be a potential strategy for the prevention or treatment of cognitive impairment in BDE-47-induced neurotoxicity and brain diseases.