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

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

  • Brain Behav Immun. 2017 Oct;65:99-110. doi: 10.1016/j.bbi.2017.05.014.
Juan Zhuang 1,  Xin Wen 2,  Yan-Qiu Zhang 3,  Qun Shan 4,  Zi-Feng Zhang 2,  Gui-Hong Zheng 2,  Shao-Hua Fan 2,  Meng-Qiu Li 2,  Dong-Mei Wu 2,  Bin Hu 2,  Jun Lu 5,  Yuan-Lin Zheng 6
Affiliations

Affiliations

  • 1 School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China; Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Science, Huaiyin Normal University, 111 Changjiang Road, Huaian 223300, Jiangsu Province, PR China.
  • 2 Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
  • 3 School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China.
  • 4 School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China.
  • 5 Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: [email protected].
  • 6 Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: [email protected].
PMID: 28532818 DOI: 10.1016/j.bbi.2017.05.014
Abstract

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.

Keywords

Cognitive impairment; NLRP3 inflammasome; Parkin; Polybrominated diphenyl ethers; TDP-43.

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