Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease
Alzheimer’s disease is a chronic neurodegenerative disorder characterized by progressive memory loss and a significant impact on quality of life. The APOE ε4 allele is a major genetic contributor to AD pathogenesis, with synaptic dysfunction being a central hallmark in its pathophysiology. While the...
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2025-02-01
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| author | Yuqing Wang Xuefeng Liu Pengtao Zheng Qing Xie Chenxiang Wang Chaoyang Pang |
| author_facet | Yuqing Wang Xuefeng Liu Pengtao Zheng Qing Xie Chenxiang Wang Chaoyang Pang |
| author_sort | Yuqing Wang |
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| description | Alzheimer’s disease is a chronic neurodegenerative disorder characterized by progressive memory loss and a significant impact on quality of life. The APOE ε4 allele is a major genetic contributor to AD pathogenesis, with synaptic dysfunction being a central hallmark in its pathophysiology. While the role of APOE4 in reducing SNARE protein levels has been established, the underlying molecular mechanisms of this interaction remain obscure. Our research employs molecular dynamics simulations to analyze interactions between APOE4 and APOE3 isoforms and the synaptic proteins VAMP2, SNAP25, and SYNTAXIN1, which play crucial roles in the presynaptic membrane. Our findings reveal that APOE4 significantly destabilizes the SNARE complex, suppresses its structural dynamics, and reduces hydrogen bonding, consequently partially hindering neurotransmitter release—a very likely discovery for elucidating synaptic dysfunction in Alzheimer’s disease. We identified that APOE4 exhibits a diminished affinity for the SNARE complex in comparison to APOE3. This observation suggests that APOE4 may play a role in modulating the stability of the SNARE complex, potentially impacting the progression and occurrence of Alzheimer’s disease through free energy analysis. This work highlights the perturbations in synaptic function mediated by APOE4, which may offer novel insights into the molecular underpinnings of AD. By elucidating the molecular interplay between APOE4 and the SNARE complex, our study not only enhances our comprehension of AD’s synaptic pathology but also paves the way for devising innovative therapeutic interventions, such as targeting the APOE4–SNARE complex interaction or to restore neurotransmitter release. |
| format | Article |
| id | doaj-art-53f9b3bb5b0a47828e127724807bdd55 |
| institution | DOAJ |
| issn | 2075-1729 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-53f9b3bb5b0a47828e127724807bdd552025-08-20T03:12:22ZengMDPI AGLife2075-17292025-02-0115222310.3390/life15020223Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s DiseaseYuqing Wang0Xuefeng Liu1Pengtao Zheng2Qing Xie3Chenxiang Wang4Chaoyang Pang5School of Physics, Chengdu University of Technology, Chengdu 610059, ChinaSchool of Physics, Chengdu University of Technology, Chengdu 610059, ChinaCollege of Computer Science, Sichuan Normal University, Chengdu 610101, ChinaSchool of Physics, Chengdu University of Technology, Chengdu 610059, ChinaSchool of Physics, Chengdu University of Technology, Chengdu 610059, ChinaCollege of Computer Science, Sichuan Normal University, Chengdu 610101, ChinaAlzheimer’s disease is a chronic neurodegenerative disorder characterized by progressive memory loss and a significant impact on quality of life. The APOE ε4 allele is a major genetic contributor to AD pathogenesis, with synaptic dysfunction being a central hallmark in its pathophysiology. While the role of APOE4 in reducing SNARE protein levels has been established, the underlying molecular mechanisms of this interaction remain obscure. Our research employs molecular dynamics simulations to analyze interactions between APOE4 and APOE3 isoforms and the synaptic proteins VAMP2, SNAP25, and SYNTAXIN1, which play crucial roles in the presynaptic membrane. Our findings reveal that APOE4 significantly destabilizes the SNARE complex, suppresses its structural dynamics, and reduces hydrogen bonding, consequently partially hindering neurotransmitter release—a very likely discovery for elucidating synaptic dysfunction in Alzheimer’s disease. We identified that APOE4 exhibits a diminished affinity for the SNARE complex in comparison to APOE3. This observation suggests that APOE4 may play a role in modulating the stability of the SNARE complex, potentially impacting the progression and occurrence of Alzheimer’s disease through free energy analysis. This work highlights the perturbations in synaptic function mediated by APOE4, which may offer novel insights into the molecular underpinnings of AD. By elucidating the molecular interplay between APOE4 and the SNARE complex, our study not only enhances our comprehension of AD’s synaptic pathology but also paves the way for devising innovative therapeutic interventions, such as targeting the APOE4–SNARE complex interaction or to restore neurotransmitter release.https://www.mdpi.com/2075-1729/15/2/223Alzheimer’s diseasesynaptic dysfunctionapolipoprotein Emolecular dynamics simulationsSNARE complexmolecular mechanics Poisson–Boltzmann surface area |
| spellingShingle | Yuqing Wang Xuefeng Liu Pengtao Zheng Qing Xie Chenxiang Wang Chaoyang Pang Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease Life Alzheimer’s disease synaptic dysfunction apolipoprotein E molecular dynamics simulations SNARE complex molecular mechanics Poisson–Boltzmann surface area |
| title | Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease |
| title_full | Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease |
| title_fullStr | Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease |
| title_full_unstemmed | Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease |
| title_short | Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer’s Disease |
| title_sort | molecular dynamics of apolipoprotein genotypes apoe4 and snare family proteins and their impact on alzheimer s disease |
| topic | Alzheimer’s disease synaptic dysfunction apolipoprotein E molecular dynamics simulations SNARE complex molecular mechanics Poisson–Boltzmann surface area |
| url | https://www.mdpi.com/2075-1729/15/2/223 |
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