Li Yixian, Yang Peng, Meng Ran, Xu Shuting, Zhou Lingling, Qian Kang, Wang Pengzhen, Cheng Yunlong, Sheng Dongyu, Xu Minjun, Wang Tianying, Wu Jing, Cao Jinxu, Zhang Qizhi
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
Acta Pharm Sin B. 2024 Mar;14(3):1380-1399. doi: 10.1016/j.apsb.2023.10.009. Epub 2023 Oct 21.
Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting A phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.
阿尔茨海默病（AD）中神经元内蛋白质稳态失衡和神经元外微环境异常共同导致神经元退化。在AD背景下，自噬功能障碍是一个涉及神经元/小胶质细胞中自噬下调和溶酶体缺陷的多环节障碍，与神经元内/外病理过程高度相关。因此，在双靶点（神经元和小胶质细胞）共同调控“自噬诱导”和“溶酶体降解”的多维自噬调节策略对AD治疗更可靠。据此，我们设计了一种负载雷帕霉素或绞股蓝皂苷XVII的RP-1肽修饰的活性氧（ROS）响应性胶束（RT-NM）。在晚期糖基化终产物受体（RAGE）的配体RP-1肽的引导下，RT-NM有效地靶向AD病变区域的神经元和小胶质细胞。这种纳米联合疗法通过自噬诱导（雷帕霉素）和溶酶体改善（绞股蓝皂苷XVII）激活整个自噬-溶酶体途径，从而增强神经毒性聚集体和炎性小体的自噬降解，并促进A吞噬作用。结果，它降低了异常蛋白负荷，减轻了神经炎症，并最终改善了3×Tg-AD转基因小鼠的记忆缺陷。我们的研究开发了一种多维自噬纳米调节剂，以提高以自噬为中心的AD治疗的疗效。
