COG-1410

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.

Discovering new drugs for ischemic stroke is an effective intervention that may address the significant unmet clinical need of stroke. There is increasing evidence indicating that apolipoprotein E (ApoE) can be a potential candidate for the treatment of ischemic stroke. A short ApoE peptide could maintain the anti‐inflammation and neuroprotection of the intact protein. Herein, we synthetized a novel ApoE memetic peptide, referred to as CS15, and explored its efficacy and neuroprotection of its innovative formulation of gold nanoparticles (GNPs) in transient focal ischemia in rat.

We examined anti‐inflammatory activities of CS15 using LPS‐induced inflammatory response in BV2 cells and in mice. GNPs were prepared by citrate reduction method and surface modified with CS15 to generate CS15‐coated GNPs (CS15‐GNPs). The accumulation and distribution of CS15‐GNPs in the brain were confirmed by detecting the gold amount and fluorescent intensity. The neuroprotection of CS15 and CS15‐GNPs was evaluate using middle cerebral artery occlusion (MCAO) model.

The results showed that CS15 exhibited more potent anti‐inflammation than COG1410. GNPs are capable of transporting CS15 to the brain, expanding its duration of action. Intranasal administration of CS15‐GNPs notably reduced infarct size and neuronal damage, improved neurological function and inhibited cerebral inflammation in transient focal ischemia in rat, which had much higher efficiency than free CS15.

CS15‐GNPs exhibited favorable neuroprotection and biosafety. This study develops an innovative ApoE‐mimetic peptide‐capped GNPs, which provides a potential strategy for the treatment of ischemic stroke.