3 years ago

Adeno-associated virus vector-mediated expression of DJ-1 attenuates learning and memory deficits in 2, 2´, 4, 4´-tetrabromodiphenyl ether (BDE-47)-treated mice

Evidence indicates that oxidative stress is the central pathological feature of 2, 2´, 4, 4´-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity. Protein kinase C delta (PKCδ), an oxidative stress-sensitive kinase, can be proteolytically cleaved to yield a catalytically active fragment (PKCδ-CF) that is involved in various neurodegenerative disorders. Here, we showed that BDE-47 treatment increased ROS, malondialdehyde, and protein carbonyl levels in the mouse hippocampus. In turn, excessive ROS induced caspase-3-dependent PKCδ activation and stimulated NF-κB p65 nuclear translocation, resulting in inflammation in the mouse hippocampus. These changes caused learning and memory deficits in BDE-47-treated mice. Treatment with Z-DEVD-fmk, a caspase-3 inhibitor, or N-acetyl-L-cysteine, an antioxidant, blocked PKCδ activation and subsequently inhibited inflammation, thereby improving learning and memory deficits in BDE-47-treated mice. Our data further showed that activation of ROS-PKCδ signaling was associated with DJ-1 downregulation, which exerted neuroprotective effects against oxidative stress induced by different neurotoxic agents. Adeno-associated viral vector-mediated DJ-1 overexpression in the hippocampus effectively inhibited excessive ROS production, suppressed caspase-3-dependent PKCδ cleavage, blunted inflammation and ultimately reversed learning and memory deficits in BDE-47-treated mice. Taken together, our results demonstrate that DJ-1 plays a pivotal role in BDE-47-induced neurotoxic effects and learning and memory deficits.

Publisher URL: www.sciencedirect.com/science

DOI: S0304389418300086

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