TREM2 Modulates Postoperative Cognitive Function in Aged Mice by Inhibiting the NLRP3/caspase-1 Pathway and Apoptosis
Xinyue Zhang1, Renyi Wang1, Xue Pan1
1Department of Anesthesiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.
Abstract:
Postoperative cognitive dysfunction (POCD) is a prevalent complication in elderly patients, with neuroinflammation identified as a key contributing factor. This study investigates the therapeutic potential of the TREM2-PLCγ2 signaling pathway in mitigating neuroinflammation, neuronal apoptosis and cognitive impairment following surgery. We employed both in vivo and in vitro models to investigate the effects of TREM2 activation and its interaction with PLCγ2. Mice subjected to surgery were pre-treated with the TREM2-activating peptide COG1410, and subsequently evaluated for neuroinflammation, neuronal apoptosis, and cognitive function. In vitro studies using microglial cells were conducted to examine the mechanistic relationship between TREM2 and PLCγ2 phosphorylation via SYK. Knockdown experiments and SYK inhibition were performed to determine the hierarchical interaction between TREM2, PLCγ2, and their downstream influence on the NLRP3 inflammasome. Surgery significantly elevated the activation of the NLRP3 inflammasome, along with increased Cleaved Caspase-1, IL-1β, IL-18, and neuronal apoptosis markers. Pre-treatment with COG1410 effectively reduced these pro-inflammatory and pro-apoptotic markers, while alleviating cognitive impairment. TREM2 activation promoted SYK-dependent phosphorylation of PLCγ2, which inhibited NLRP3 inflammasome activation and reduced neuroinflammation. TREM2 knockdown exacerbated microglial inflammation, while PLCγ2 knockdown suppressed NLRP3 activation. Inhibition of SYK impaired the protective effects of the TREM2-PLCγ2 pathway and delayed cognitive recovery in mice. RNA-sequencing further revealed significant alterations in pathways related to neuroinflammation and apoptosis. TREM2 modulates PLCγ2 activity through SYK phosphorylation, thereby alleviating microglial-driven neuroinflammation and neuronal apoptosis, and improving cognitive impairment following surgery. Targeting the TREM2-PLCγ2 pathway presents a promising strategy for the prevention and treatment of POCD.
