TNFα-NALP3炎症小体调节小胶质细胞-星型胶质细胞协同清除Aβ作用机制研究

Decreased Amyloid beta (Aβ) clearance ability plays a critical role in the pathogenesis of Alzheimer's disease (AD). Up-regulation of Aβ clearance has become a new research strategy in AD therapy, but anti-Aβ immunotherapies have failed in many clinical trials. In preliminary work (NSFC 30700248), we found that anti-tumor necrosis factor α (TNFα) monoclonal antibody (Infliximab) could rapidly reduce Aβ deposition in AD transgenic mice and improve cognition. On the basis of research focusing on the defective Aβ clearance ability of microglia (MG) and astrocytes (AC) in AD, we found that Infliximab could inhibit the activation of Aβ-induced NALP3 inflammasone in MG and regulate the crosstalk between MG and AC. We put forward the hypothesis that selectively inhibiting the TNFα pathway could promote Aβ clearance by regulating MG-AC crosstalk. By RNAi, live cell imaging technique, the aim is to reveal the relationship between inhibition of TNFα and activation of NALP3 inflammatory, to clarify the mechanism of TNFα inhibition regulating MG-AC interaction and further to elaborate the principle of targeting TNFα on promoting Aβ clearance. It will provide a basis to explore the mechanism of MG-AC's co-clearing Aβ and to explore a new strategy for AD therapy.

淀粉样蛋白β(Aβ)清除能力下降是阿尔茨海默病(AD)的重要发病机制，促进Aβ清除成为AD研究新策略，但靶向Aβ诸多免疫治疗均未成功。我们在前期工作(30700248)中发现：抗肿瘤坏死因子α(TNFα)单抗Infliximab能迅速减轻AD模型鼠Aβ沉积，改善认知；在国内外研究提示AD的小胶质细胞(MG)、星型胶质细胞(AC)清除Aβ能力下降基础上，预实验发现Infliximab能抑制MG中Aβ导致的NALP3炎症小体激活，调节MG-AC交互作用。我们提出此假说：选择性干预TNFα途径可以调节MG-AC交互作用从而促进Aβ的清除。研究将通过RNAi、活细胞成像等技术揭示靶向抑制TNFα与NALP3炎症小体激活的关系，阐明靶向抑制TNFα调控MG-AC交互作用的机制，并进一步阐明该机制促进Aβ清除的原理；将为探索MG-AC协同清除Aβ的机制提供依据，为寻找AD防治策略开拓新思路。

我们在前期工作(30700248)中已经证实抗肿瘤坏死因子 α(TNFα)单抗 Infliximab 能迅速减轻 AD 模型鼠 Aβ 沉积，改善认知；其机制与抑制Aβ-小胶质细胞(MG)的 NALP3 炎症小体激活途径有关。进一步通过 RNAi、活细胞成像等技术的体内外动物模型研究首次揭示青蒿素等可以靶向抑制 TNFα 与 NALP3 炎症小体激活，包括：1). 对Aβ的β分泌酶途径，Tau的磷酸化，以及Aβ的内淋巴清除存在明确的调控作用(新发现);2). 沉默MG-ASC可以直接下调MG-AC细胞间TNFα-NALP3炎症途径；3). 而沉默AC-ASC则诱导MG相关CSF1R表达下调，MG的炎性转化下调(新发现)。上述研究结果阐明了靶向抑制TNFα 调控MG-AC 交互作用的机制，多途径促进 Aβ 清除主要依赖于MG-AC 协同机制，不仅为靶向MG-AC细胞间TNFα-NALP3炎症途径的机制阐明积累了学术基础，也为阿尔茨海默病等神经退变疾病的治疗药物的研发提供了新靶标和候选药物，进而为AD的临床治疗提供新的有益思路。