Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

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外文摘要：Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alz-heimer'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(rapamy-cin)and lysosome improvement(gypenoside ⅩⅦ),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant pro-tein 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 effi-cacy of autophagy-centered AD therapy.

外文关键词：

Autophagy-lysosome pathwayAlzheimer's diseaseProteostasisNeuroinflammationMulti-target therapyRapamycinGypenoside ⅩⅦCascade dual-targeting

作者：

Yixian Li、Peng Yang、Ran Meng、Shuting Xu、Lingling Zhou、Kang Qian、Pengzhen Wang、Yunlong Cheng、Dongyu Sheng、Minjun Xu、Tianying Wang、Jing Wu、Jinxu Cao、Qizhi Zhang

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作者单位：

Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,Shanghai 201203,China

基金：

国家自然科学基金国家自然科学基金上海市自然科学基金staff members of the Integrated Laser Microscopy System at the National Facility for Protein Science in Shanghai(NFPS)Shanghai Advanced Research Institute,Chinese Academy of Sciences,China for sample preparation,data collection and analysis

项目编号：

820737808227386819ZR1406200

出版年：

2024

DOI：

10.1016/j.apsb.2023.10.009

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(3)

参考文献量60