新加坡南洋理工大学Zhao Yanli 研究团队报道了自增强的“小胶质细胞能量调节剂”，用于阿尔茨海默病模型中协同淀粉样蛋白β清除。相关研究成果发表在2024年12月23日出版的《德国应用化学》。

小胶质细胞吞噬是一个高度耗能的过程，在清除阿尔茨海默病（AD）中的神经毒性淀粉样蛋白-β（aβ）方面起着关键作用。然而，AD患者的小胶质细胞代谢总体上存在缺陷，从而破坏了小胶质细胞的吞噬功能。

该文中，研究人员将现有的抗肿瘤药物洛尼达明（LND）与中空介孔普鲁士蓝（HMPB）结合，作为“小胶质细胞能量调节剂”（称为LND@HMPB-T7)用于安全和协同的Aβ清除。经修饰的血脑屏障穿透七肽（T7）能够有效运输LND@HMPB-T7到AD大脑。

LND@HMPB-T7中的LND可以通过刺激小胶质细胞三磷酸腺苷（ATP）的产生，来促进Aβ吞噬作用，而具有过氧化氢酶和超氧化物歧化酶模拟活性的HMPB，大大减轻了通常与LND相关的线粒体副作用，从而进一步增强了ATP的产生。

LND和纳米酶的协同作用提供了高的小胶质细胞aβ清除效率，而不会引发线粒体功能障碍。体内实验证实LND@HMPB-T7能协同促进AD小鼠Aβ的吞噬清除，缓解神经炎症，改善认知功能。这些发现表明LND@HMPB-T7作为AD治疗的再利用药物，具有巨大的临床潜力。

附：英文原文

Title: A Self-Reinforced “Microglia Energy Modulator” for Synergistic Amyloid-β Clearance in Alzheimer’s Disease Model

Author: Mengmeng Ma, Jing Wang, Kaiming Guo, Wenbin Zhong, Yu Cheng, Li Lin, Yanli Zhao

Issue&Volume: 2024-12-23

Abstract: Microglial phagocytosis is a highly energy-consuming process that plays critical roles in clearing neurotoxic amyloid-β (Aβ) in Alzheimer’s disease (AD). However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a “microglial energy modulator” (termed LND@HMPB-T7) for safe and synergistic Aβ clearance. The modified blood-brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB-T7 to the AD brain. LND in LND@HMPB-T7 could fuel Aβ phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase-mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial Aβ clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB-T7 could synergistically promote phagocytic clearance of Aβ, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB-T7 holds tremendous clinical potential as a repurposed drug for AD treatment.

DOI: 10.1002/anie.202420547

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202420547