Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease
Abstract A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β‐amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IH...
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202303411 |
| _version_ | 1797627752052948992 |
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| author | Xiaotong Wang Rui Zhou Xiaqin Sun Jun Li Jinxin Wang Weihua Yue Lifang Wang Hesheng Liu Yigong Shi Dai Zhang |
| author_facet | Xiaotong Wang Rui Zhou Xiaqin Sun Jun Li Jinxin Wang Weihua Yue Lifang Wang Hesheng Liu Yigong Shi Dai Zhang |
| author_sort | Xiaotong Wang |
| collection | DOAJ |
| description | Abstract A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β‐amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme‐linked immune‐sorbent assay (ELISA). Cryo‐electron microscopy (Cryo‐EM) is used to determine the structure of γ‐secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ‐secretase structure and specifically accelerates γ‐secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N‐terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ‐secretase activity and the pathogenesis of AD. |
| first_indexed | 2024-03-11T10:28:47Z |
| format | Article |
| id | doaj.art-93404aa7e3f34b29b562184fa4160ed6 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T10:28:47Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-93404aa7e3f34b29b562184fa4160ed62023-11-15T05:46:35ZengWileyAdvanced Science2198-38442023-11-011032n/an/a10.1002/advs.202303411Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's DiseaseXiaotong Wang0Rui Zhou1Xiaqin Sun2Jun Li3Jinxin Wang4Weihua Yue5Lifang Wang6Hesheng Liu7Yigong Shi8Dai Zhang9Peking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaBeijing Frontier Research Center for Biological Structure Tsinghua‐Peking Joint Center for Life Sciences School of Life Sciences Tsinghua University Beijing 100084 ChinaPeking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaPeking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaState Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research Beijing Normal University Beijing 100875 ChinaPeking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaPeking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaChangping Laboratory Beijing 102206 ChinaBeijing Frontier Research Center for Biological Structure Tsinghua‐Peking Joint Center for Life Sciences School of Life Sciences Tsinghua University Beijing 100084 ChinaPeking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health (Peking University) National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 ChinaAbstract A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β‐amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme‐linked immune‐sorbent assay (ELISA). Cryo‐electron microscopy (Cryo‐EM) is used to determine the structure of γ‐secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ‐secretase structure and specifically accelerates γ‐secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N‐terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ‐secretase activity and the pathogenesis of AD.https://doi.org/10.1002/advs.202303411Alzheimer's diseaseconformationganglioside GM1presenilin1β‐amyloid protein |
| spellingShingle | Xiaotong Wang Rui Zhou Xiaqin Sun Jun Li Jinxin Wang Weihua Yue Lifang Wang Hesheng Liu Yigong Shi Dai Zhang Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease Advanced Science Alzheimer's disease conformation ganglioside GM1 presenilin1 β‐amyloid protein |
| title | Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease |
| title_full | Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease |
| title_fullStr | Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease |
| title_full_unstemmed | Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease |
| title_short | Preferential Regulation of Γ‐Secretase‐Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease |
| title_sort | preferential regulation of γ secretase mediated cleavage of app by ganglioside gm1 reveals a potential therapeutic target for alzheimer s disease |
| topic | Alzheimer's disease conformation ganglioside GM1 presenilin1 β‐amyloid protein |
| url | https://doi.org/10.1002/advs.202303411 |
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