NEK7 inhibition attenuates Aβ42-induced cognitive impairment by regulating TLR4/NF-κB and the NLRP3 inflammasome in mice.

Abstract

NEK7 is a serine/threonine kinase that regulates cell mitosis and the activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, and is related to neuroinflammation and neuronal damage. The purpose of this study was to explore the role and mechanism of NEK7 in cognitive impairment in Alzheimer's disease (AD). BV2 cells, a microglia cell line, was treated with Aβ₄₂. NEK7 expression was measured with reverse transcription-quantitative polymerase chain reaction and Western blotting. An apoptosis kit was used to determine the apoptotic rate. APPswe/PS1dE9 (APP/PS1) transgenic mice were used as an in vivo AD model. The experimental mice were infected with sh-NEK7 lentivirus to downregulate NEK7. The Morris water maze was conducted to explore the effect of NEK7 downregulation on cognitive ability. The results showed that Aβ₄₂ significantly upregulated NEK7 in BV2 cells. Silencing NEK7 suppressed the decrease in BV2 viability and the increase in inflammation, oxidative stress and apoptosis induced by Aβ₄₂. NEK7 mediated it effects through the TLR4/NF-κB signalling pathway and the NLRP3 inflammasome. Finally, inhibition of NEK7 alleviated the cognitive impairment in APP/PS1 mice. In conclusion, Silencing NEK7 suppresses Aβ₄₂-induced cell apoptosis, inflammation and oxidative stress, and improves cognitive performance in AD mice. NEK7 may be a potential target for AD treatment.