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BACE1 controls synaptic function through modulating release of synaptic vesicles
BACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer’s disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ deposition, they fail to improve cognitive function in patients, large...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760050/ https://www.ncbi.nlm.nih.gov/pubmed/34158621 http://dx.doi.org/10.1038/s41380-021-01166-2 |
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author | Das, Brati Singh, Neeraj Yao, Annie Y. Zhou, John He, Wanxia Hu, Xiangyou Yan, Riqiang |
author_facet | Das, Brati Singh, Neeraj Yao, Annie Y. Zhou, John He, Wanxia Hu, Xiangyou Yan, Riqiang |
author_sort | Das, Brati |
collection | PubMed |
description | BACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer’s disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients. |
format | Online Article Text |
id | pubmed-8760050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87600502022-01-26 BACE1 controls synaptic function through modulating release of synaptic vesicles Das, Brati Singh, Neeraj Yao, Annie Y. Zhou, John He, Wanxia Hu, Xiangyou Yan, Riqiang Mol Psychiatry Article BACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer’s disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients. Nature Publishing Group UK 2021-06-22 2021 /pmc/articles/PMC8760050/ /pubmed/34158621 http://dx.doi.org/10.1038/s41380-021-01166-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Das, Brati Singh, Neeraj Yao, Annie Y. Zhou, John He, Wanxia Hu, Xiangyou Yan, Riqiang BACE1 controls synaptic function through modulating release of synaptic vesicles |
title | BACE1 controls synaptic function through modulating release of synaptic vesicles |
title_full | BACE1 controls synaptic function through modulating release of synaptic vesicles |
title_fullStr | BACE1 controls synaptic function through modulating release of synaptic vesicles |
title_full_unstemmed | BACE1 controls synaptic function through modulating release of synaptic vesicles |
title_short | BACE1 controls synaptic function through modulating release of synaptic vesicles |
title_sort | bace1 controls synaptic function through modulating release of synaptic vesicles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760050/ https://www.ncbi.nlm.nih.gov/pubmed/34158621 http://dx.doi.org/10.1038/s41380-021-01166-2 |
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