Dongju Zhao , Fan Yang , Yining Liu , Meng Cheng , Ziyao Chen , Caihua Ye , Jin Chang , Yan Dou
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引用次数: 0
摘要
慢性神经微血管功能障碍及其诱发的多方面神经病理学涉及细胞不同致病机制的相互作用,给阿尔茨海默病(AD)的精确治疗带来了挑战。在这里,我们报告了一种鞣花酸衍生自组装胶束 SIRT1 激活剂(REn)的开发情况,这种激活剂能对 AD 的神经血管和神经代谢耦合进行跨尺度的靶向重塑。通过修饰肽对高级糖化终产物受体的高效转囊作用,可将 REn 按程序输送到脑微血管和实质神经元。由此激活的 SIRT1 级联可增强内皮一氧化氮信号介导的脑血流量和血脑屏障的完整性,同时促进神经元线粒体生物生成和葡萄糖代谢模式向氧化磷酸化方向发展。这种多管齐下的重塑策略实现了AD小鼠大脑能量供应和β-淀粉样蛋白清除的协同正常化,并显著改善了认知障碍。这项工作为与神经血管功能障碍相关的神经退行性疾病的跨规模靶向治疗提供了一种先进的药理学选择。
Cross-scale targeted remodeling of neurovascular and neurometabolic coupling in Alzheimer’s disease by natural self-assembled SIRT1 activator
Chronic neuromicrovascular dysfunction and its induced multifaceted neuropathology involving the interaction of cellular differential pathogenic mechanisms pose challenges to the precise treatment of Alzheimer’s disease (AD). Here we report the development of an ellagic acid-derived self-assembled micellar SIRT1 activator (REn) that enables cross-scale targeted remodeling of neurovascular and neurometabolic coupling in AD. Efficient transcytosis of the receptor for advanced glycation endproducts by modified peptides allows for programmed delivery of REn to cerebral microvessels and parenchymal neurons. The resulting SIRT1 cascade activation enhances endothelial nitric oxide signaling-mediated cerebral blood flow and the blood-brain barrier integrity, while promoting neuronal mitochondrial biogenesis and glucose metabolic patterns toward oxidative phosphorylation. This multipronged remodeling strategy achieves a cooperative normalization of brain energy supply and β-amyloid clearance in AD mice, showing profound improvement in cognitive impairment. This work provides an advanced pharmacological option for cross-scale targeted treatment of neurodegenerative diseases associated with neurovascular dysfunction.
期刊介绍:
Nano Today is a journal dedicated to publishing influential and innovative work in the field of nanoscience and technology. It covers a wide range of subject areas including biomaterials, materials chemistry, materials science, chemistry, bioengineering, biochemistry, genetics and molecular biology, engineering, and nanotechnology. The journal considers articles that inform readers about the latest research, breakthroughs, and topical issues in these fields. It provides comprehensive coverage through a mixture of peer-reviewed articles, research news, and information on key developments. Nano Today is abstracted and indexed in Science Citation Index, Ei Compendex, Embase, Scopus, and INSPEC.