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Updated: Jun 4, 2025
Characterization of Neuronal Lysosome Interactome with Proximity Labeling Proteomics
Published on: June 23, 2022
Lysosome-Targeting Protein Degradation Through Endocytosis Pathway Triggered by Polyvalent Nano-Chimera for AD
Xiaorong Wang1, Shiqin Chen1, Xue Xia1
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Abstract:
The excessive up-regulation of receptor for advanced glycation end products (RAGE), a well-known pathological marker, drives the onset and progression of Alzheimer's disease. Although lysosome-targeting protein degradation has emerged as an effective therapeutic modality, the limited lysosome-sorting efficacy greatly hindered the degradation efficiency of target proteins. Herein, a lysosome-shuttle-like nano-chimera (endoTAC) is proposed based on polyvalent receptor binding mode for enhanced RAGE degradation as well as precise drug delivery. The endoTAC shows a high affinity to RAGE and enhances RAGE degradation due to its polyvalent-interaction with RAGE. Additionally, endoTAC features increased accumulation in diseased brain and shows promise as a precise brain delivery system. After loading with simvastatin, the SV@endoTAC proves to successfully reverse pathological features both in vitro and in vivo. The work proposes that the combination of a lysosome-targeting chimera and an effective drug delivery system can be promising in Alzheimer's disease therapy.
Insights
A novel nano-chimera (endoTAC) enhances degradation of the Alzheimer's marker RAGE by targeting lysosomes. This system also delivers drugs precisely to the brain, reversing disease pathology.
Area of Science:
- Biomedical Engineering
- Neuroscience
- Drug Delivery Systems
Background:
- Upregulation of the receptor for advanced glycation end products (RAGE) is a key driver in Alzheimer's disease pathogenesis.
- Lysosome-targeting protein degradation shows therapeutic potential but is limited by inefficient lysosome-sorting.
- Targeting RAGE is a promising strategy for Alzheimer's disease therapy.
Purpose of the Study:
- To develop a lysosome-shuttle-like nano-chimera (endoTAC) for enhanced RAGE degradation.
- To evaluate endoTAC's efficacy as a precise drug delivery system for the brain.
- To investigate the therapeutic potential of combining lysosome-targeting with drug delivery for Alzheimer's disease.
Main Methods:
- Design of a nano-chimera (endoTAC) utilizing a polyvalent receptor binding mode for RAGE.
- Assessment of endoTAC's affinity and RAGE degradation enhancement in vitro.
- Evaluation of endoTAC's brain accumulation and drug delivery capabilities in vivo.
- Loading simvastatin onto endoTAC (SV@endoTAC) and testing its therapeutic effects.
Main Results:
- EndoTAC demonstrated high affinity for RAGE, significantly enhancing its degradation via polyvalent interactions.
- EndoTAC showed increased accumulation in diseased brain tissue, validating its potential as a brain delivery system.
- SV@endoTAC effectively reversed pathological features in both in vitro and in vivo Alzheimer's models.
Conclusions:
- The developed endoTAC nano-chimera effectively targets and degrades RAGE, a key Alzheimer's marker.
- EndoTAC serves as a promising platform for precise drug delivery to the brain.
- Combining lysosome-targeting strategies with effective drug delivery systems offers a potent therapeutic approach for Alzheimer's disease.
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