基于线粒体自噬治疗阿尔茨海默病的药物研究进展

Advancements in research Mitophagy-based Drugs in Alzheimer's Disease

关键词:  阿尔茨海默病  线粒体自噬  药物  PINK1/Parkin通路  新型制剂

Key words:  Alzheimer's disease  mitophagy  drugs  PINK1/Parkin  novel formulations

摘要:

随着全球老龄化进程加速，阿尔茨海默病（AD）的疾病负担持续攀升，然而现有疗法仍局限于症状缓解，缺乏针对疾病核心病理机制的根治性策略。线粒体自噬作为清除损伤线粒体、维持大脑能量稳态的关键机制，其功能异常已被证实是AD病理进展的核心驱动因素之一。本文首先阐述AD中Aβ沉积、Tau蛋白过度磷酸化与线粒体自噬障碍的相互作用机制，随后系统综述了靶向线粒体自噬的AD治疗干预手段：包括通过PINK1/Parkin通路、受体介导型通路直接激活线粒体自噬，以及通过调控上游节点、恢复线粒体形态、维持线粒体稳态、改善溶酶体功能间接促进线粒体自噬的小分子化合物、天然产物及非药物疗法，进一步梳理了具有血脑屏障穿透优势的新型纳米制剂与生物制剂的研究进展，最后总结当前研究瓶颈，并对靶向线粒体自噬的AD药物临床转化方向进行展望，为开发高效AD防治方案提供新思路。

Abstract:

With the acceleration of global aging, the disease burden of Alzheimer's disease (AD) continues to rise. However, current therapy remains limited to symptomatic relief, and curative strategies that directly target the core pathological mechanisms are still lacking. Mitophagy, a critical process for clearing damaged mitochondria and maintaining cerebral energy homeostasis, has been closely linked to the pathological progression of AD. This paper first elucidates the interactive mechanisms among Aβ deposition, tau hyperphosphorylation, and impaired mitophagy in AD. followed by a systematic review of therapeutic interventions targeting mitophagy in AD. These include direct activation of mitophagy via the PINK1/Parkin pathway and receptor-mediated pathways, as well as indirect promotion through small molecules, natural products, and non-pharmaceutical therapies that indirectly promote mitophagy by regulating upstream nodes, restoring mitochondrial morphology, maintaining mitochondrial homeostasis, and improving lysosomal function. It further reviews research progress on novel nanomedicines and biologics with blood-brain barrier penetration advantages. Finally, it summarizes current research bottlenecks and outlines prospects for the clinical translation of AD drugs targeting mitophagy, providing new insights for developing effective AD prevention and treatment strategies.