锦葵提取物通过 PPAR-γ 依赖的机制恢复小胶质细胞功能，从而改善高脂肪饮食对阿尔茨海默病小鼠模型认知功能障碍的有害影响。

BACKGROUND: Alzheimer's disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties. METHODS: The present study was aimed to determine the anti-inflammatory potential of M. parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid β (Aβ) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC. RESULTS: MpHE efficiently reduced astrogliosis, the presence of insoluble Aβ peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aβ plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals. CONCLUSIONS: M. parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M. parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression.

背景：阿尔茨海默病（AD）是一种与炎症途径激活密切相关的神经病理学。因此，肥胖引起的炎症会加剧人类和 AD 动物模型的学习和记忆缺陷。因此，长期使用非甾体抗炎药会降低患 AD 的风险，但这些药物的副作用限制了它们的预防用途。因此，植物天然产物已成为现代治疗的绝佳选择。Malva parviflora 是一种以其抗炎特性而闻名的植物。

方法：本研究旨在确定 Malva parviflora 叶水醇提取物（MpHE）对 lean 和肥胖转基因 5XFAD 小鼠（家族性 AD 的模型）AD 病理学的抗炎潜力。通过免疫定位（Iba-1 和 GFAP）和 RT-qPCR（TNF）测定以及硫代黄素-S 染色分别评估 lean 和肥胖 5XFAD 小鼠未经处理或用 MpHE 处理后的炎症反应和淀粉样β（Aβ）斑块负荷。通过 Morris 水迷宫行为测试评估空间学习记忆。体内、体外和体外测定分析小胶质细胞吞噬能力，并通过形态变化（鬼笔环肽染色）和 RT-qPCR（CD86、Mgl1 和 TREM-2）评估其激活。通过免疫印迹（PPAR-γ）和 RT-qPCR（CD36）在原代小胶质细胞培养物和离体测定中以及通过体内流式细胞术，使用 GW9662（PPAR-γ 抑制剂）和吡格列酮（PPAR-γ 激动剂），确定 MpHE 触发的机制。通过 HPLC 确定 MpHE 中的生物活性化合物。

结果：MpHE 可有效减少 lean 和肥胖 5XFAD 小鼠海马中星形胶质细胞增生、不溶性 Aβ 肽的存在以及空间学习障碍。这伴随着皮质和海马中 Aβ 斑块周围小胶质细胞的积累以及 M1 炎症标志物表达的降低。与 MpHE 通过 PPAR-γ/CD36 依赖性机制挽救小胶质细胞吞噬能力的事实一致，MpHE 含有齐墩果酸和山柰酚作为活性植物化学物质。

结论：M. parviflora 通过抑制小胶质细胞促炎 M1 表型和促进小胶质细胞吞噬作用来抑制神经炎症。因此，M. parviflora 植物化学物质可作为预防与代谢紊乱相关的认知障碍的替代方法，也是预防 AD 进展的有效候选药物。