Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss
Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ<sub>1–42</sub>) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippo...
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Xingxing Wang Qinfang Shi Arpit Kumar Pradhan Laura Ziegon Martin Schlegel Gerhard Rammes |
| author_facet | Xingxing Wang Qinfang Shi Arpit Kumar Pradhan Laura Ziegon Martin Schlegel Gerhard Rammes |
| author_sort | Xingxing Wang |
| collection | DOAJ |
| description | Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ<sub>1–42</sub>) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippocampal dendritic spine plasticity and BACE-dependent APP processing remain unclear. In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Thereafter, CA1 dendritic spine density, APP processing-related molecule expressions, nectin-3 levels, and long-term potentiation (LTP) were tested. The nectin-3 downregulation on LTP and dendritic spines were evaluated. Sevo treatment increased hippocampal mouse Aβ<sub>1–42</sub> (mAβ<sub>1–42</sub>), abolished CA1-LTP, and decreased spine density and nectin-3 expressions in the CA1 region. Furthermore, CA1-nectin-3 knockdown blocked LTP and reduced spine density. Iso treatment decreased spine density and attenuated LTP. Although Xe blocked LTP, it did not affect spine density, mAβ<sub>1–42</sub>, or nectin-3. Finally, antagonizing BACE activity partly restored sevo-induced deficits. Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling. |
| first_indexed | 2024-03-09T23:33:43Z |
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| id | doaj.art-07db0dbf9e344d03ac3f266102fb8f08 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:33:43Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-07db0dbf9e344d03ac3f266102fb8f082023-11-23T17:04:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312663710.3390/ijms23126637Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine LossXingxing Wang0Qinfang Shi1Arpit Kumar Pradhan2Laura Ziegon3Martin Schlegel4Gerhard Rammes5Department of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, GermanyEvidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ<sub>1–42</sub>) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippocampal dendritic spine plasticity and BACE-dependent APP processing remain unclear. In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Thereafter, CA1 dendritic spine density, APP processing-related molecule expressions, nectin-3 levels, and long-term potentiation (LTP) were tested. The nectin-3 downregulation on LTP and dendritic spines were evaluated. Sevo treatment increased hippocampal mouse Aβ<sub>1–42</sub> (mAβ<sub>1–42</sub>), abolished CA1-LTP, and decreased spine density and nectin-3 expressions in the CA1 region. Furthermore, CA1-nectin-3 knockdown blocked LTP and reduced spine density. Iso treatment decreased spine density and attenuated LTP. Although Xe blocked LTP, it did not affect spine density, mAβ<sub>1–42</sub>, or nectin-3. Finally, antagonizing BACE activity partly restored sevo-induced deficits. Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling.https://www.mdpi.com/1422-0067/23/12/6637isofluranesevofluranexenonsynaptic plasticityβ-site amyloid precursor protein-cleaving enzymedendritic spines |
| spellingShingle | Xingxing Wang Qinfang Shi Arpit Kumar Pradhan Laura Ziegon Martin Schlegel Gerhard Rammes Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss International Journal of Molecular Sciences isoflurane sevoflurane xenon synaptic plasticity β-site amyloid precursor protein-cleaving enzyme dendritic spines |
| title | Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss |
| title_full | Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss |
| title_fullStr | Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss |
| title_full_unstemmed | Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss |
| title_short | Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss |
| title_sort | beta site amyloid precursor protein cleaving enzyme inhibition partly restores sevoflurane induced deficits on synaptic plasticity and spine loss |
| topic | isoflurane sevoflurane xenon synaptic plasticity β-site amyloid precursor protein-cleaving enzyme dendritic spines |
| url | https://www.mdpi.com/1422-0067/23/12/6637 |
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