Wanting Zhang, Shan Wang, Xingchun Gou
The exact initiating causes of Alzheimer's disease (AD) remain inconclusive. Meanwhile, the causal sequence and interactions within its pathological network are still poorly understood, which limits the efficacy of single treatment strategies and impedes drug development. Oxidative stress, identified as a central intersection point within this network, drives the deposition of amyloid-β protein, excessive tau phosphorylation, neuroinflammation, and mitochondrial damage, creating a self-perpetuating cycle. Consequently, oxidative stress has become a focal point for multi-target interventions. This review systematically investigates the evidence of terpenoids in cellular and animal models, elucidating their protective effects via a dual antioxidant mechanism. Firstly, terpenoids activate the Keap1/Nrf2/ARE pathway, leading to the upregulation of antioxidant genes and reduced free radical generation. Secondly, they enhance PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged organelles and preventing the release of reactive oxygen species. The review also delves into the positive feedback regulatory network involving molecules like Nrf2 and key proteins of mitophagy, such as p62/SQSTM1, offering a detailed mechanistic insight into the synergistic effects of terpenoids. This study underscores the significance of natural terpenoids, with their unique regulatory role in oxidative stress, as a promising candidate library for Alzheimer's drug development due to their diverse structures, clear mechanisms, and high safety profile. Additionally, it establishes a theoretical and experimental basis for the development of novel intervention strategies targeting multiple pathways with a single drug.