Targeting LKB1–AMPK–SIRT1–induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice

作者：Yawen Li, Tongxing Wang, Hongrong Li, Yuning Jiang, Xiaogang Shen, Kang Ning, Zhifang Guo, Runtao Zhang, Xiaohong Lu, Tianyu Kang, Mengnan Li, Yunlong Hou, Yiling Wu · 发表于：Free Radical Biology and Medicine · 年份：2025 · DOI：10.1016/j.freeradbiomed.2025.03.045 · 被引用次数：18 · 研究领域：Ginseng Biological Effects and Applications、Alzheimer's disease research and treatments、Autophagy in Disease and Therapy

BACKGROUND: Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen capsule (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood. METHODS: In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon in vivo imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both in vivo and in vitro. Additionally, we employed molecular virtual docking screening and biolayer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins. RESULTS: The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood-brain barrier permeabilit...