Role of lipocalin-2 in surgery-induced cognitive decline in mice: a signal from neuron to microglia

Background Perioperative neurocognitive disorders (PNDs) are common complications observed among surgical patients. Accumulating evidence suggests that neuroinflammation is one of the major contributors to the development of PNDs, but the underlying mechanisms remain unclear. Methods qPCR and ELISA analysis were used for detecting LCN2 and cytokine levels. cx3cr1(CreER/-):: R26(iDTR/-) crossed mouse line was used for microglia depletion; intracranial injection of recombinant LCN2 (rLCN2) and adeno-associated viruses (AAV)-mediated shRNA silencing approaches were used for gain and loss of function, respectively. Combing with in vitro microglia cell culture, we have studied the role of LCN2 in surgery-induced cognitive decline in mice. Results We revealed that Lcn2 mRNA and protein levels were greatly increased in mouse hippocampal neurons after surgery. This surgery-induced elevation of LCN2 was independent of the presence of microglia. Gain of function by intracranial injection of rLCN2 protein into hippocampus disrupted fear memory in naive mice without surgery. Conversely, silencing LCN2 in hippocampus by AAV-shRNA protected mice from surgery-induced microglia morphological changes, neuroinflammation and cognitive decline. In vitro, application of rLCN2 protein induced the expression of several pro-inflammatory cytokines in both BV-2 and primary microglia culture. Conclusions These data suggest LCN2 acts as a signal from neuron to induce proinflammatory microglia, which contributes to surgery-induced neuroinflammation and cognitive decline in mice.

Automated summary

This study found that LCN2 levels were significantly increased in the hippocampus of mice after surgery, independent of microglia presence. The increase of LCN2 led to the formation of proinflammatory microglia and contributed to surgery-induced neuroinflammation and cognitive decline in mice.