The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ_1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ_1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2^−/−) were treated with fibrillary Aβ_1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and Aβ load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aβ_1-42-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFкB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load.

These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.

阿尔茨海默病 (AD) 的主要组织病理学特征包括 β-淀粉样蛋白 (Aβ) 斑块、神经原纤维缠结和神经元丢失。Aβ 1-42 (Aβ _1-42 ) 已被证明可诱导神经毒性和促炎介质的分泌，从而增强神经毒性。Aβ _1-42的促炎和神经毒性活性被证明是由与几种细胞表面受体的相互作用介导的，包括趋化 G 蛋白偶联的 N-甲酰肽受体 2 (FPR2)。本研究调查了一种新的 FPR2 激动剂 MR-39 对 AD 离体和体内模型中的神经炎症反应的影响。为了解决这个问题，来自野生型 (WT) 和 FPR2 缺陷小鼠（敲除、KO、FPR2 ^-/-) 用原纤维 Aβ _1-42治疗，并评估了新的 FPR2 激动剂 MR-39 对促炎和抗炎细胞因子释放的影响。同样，APP/PS1 双转基因 AD 小鼠用 MR-39 治疗 20 周，并进行免疫组织学染色以评估海马和皮质中的神经元丢失、神经胶质增生和 Aβ 负荷。数据表明 MR-39 能够降低 Aβ _1-42-诱导促炎细胞因子的释放并改善小鼠海马器官培养物中抗炎细胞因子的释放。观察到的效果显然与抑制 MyD88/TRAF6/NFкB 信号通路和减少 NLRP3 炎性体激活有关。给 APP/PS1 小鼠施用 MR-39 可改善神经元存活率并降低小胶质细胞密度和斑块负荷。

这些结果表明，FPR2 可能是缓解与 AD 相关的炎症过程的有希望的靶标，并且 MR-39 可能是 AD 的有用治疗剂。