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Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramida...

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Autores principales: He, Yang, Wei, Mengdi, Wu, Yan, Qin, Huaping, Li, Weinan, Ma, Xiaolin, Cheng, Jingjing, Ren, Jinshuai, Shen, Ye, Chen, Zhong, Sun, Binggui, Huang, Fu-De, Shen, Yi, Zhou, Yu-Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416269/
https://www.ncbi.nlm.nih.gov/pubmed/30867420
http://dx.doi.org/10.1038/s41467-019-09114-z
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author He, Yang
Wei, Mengdi
Wu, Yan
Qin, Huaping
Li, Weinan
Ma, Xiaolin
Cheng, Jingjing
Ren, Jinshuai
Shen, Ye
Chen, Zhong
Sun, Binggui
Huang, Fu-De
Shen, Yi
Zhou, Yu-Dong
author_facet He, Yang
Wei, Mengdi
Wu, Yan
Qin, Huaping
Li, Weinan
Ma, Xiaolin
Cheng, Jingjing
Ren, Jinshuai
Shen, Ye
Chen, Zhong
Sun, Binggui
Huang, Fu-De
Shen, Yi
Zhou, Yu-Dong
author_sort He, Yang
collection PubMed
description Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ(42) also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP(2)) in axons. Selectively inhibiting Aβ-induced PIP(2) hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP(2) pathway whereby oligomeric Aβ induces early synaptic deficits in AD.
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spelling pubmed-64162692019-03-15 Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate He, Yang Wei, Mengdi Wu, Yan Qin, Huaping Li, Weinan Ma, Xiaolin Cheng, Jingjing Ren, Jinshuai Shen, Ye Chen, Zhong Sun, Binggui Huang, Fu-De Shen, Yi Zhou, Yu-Dong Nat Commun Article Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer’s disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ(42) also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aβ-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP(2)) in axons. Selectively inhibiting Aβ-induced PIP(2) hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aβ-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP(2) pathway whereby oligomeric Aβ induces early synaptic deficits in AD. Nature Publishing Group UK 2019-03-13 /pmc/articles/PMC6416269/ /pubmed/30867420 http://dx.doi.org/10.1038/s41467-019-09114-z Text en © The Author(s) 2019 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/.
spellingShingle Article
He, Yang
Wei, Mengdi
Wu, Yan
Qin, Huaping
Li, Weinan
Ma, Xiaolin
Cheng, Jingjing
Ren, Jinshuai
Shen, Ye
Chen, Zhong
Sun, Binggui
Huang, Fu-De
Shen, Yi
Zhou, Yu-Dong
Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title_full Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title_fullStr Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title_full_unstemmed Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title_short Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
title_sort amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416269/
https://www.ncbi.nlm.nih.gov/pubmed/30867420
http://dx.doi.org/10.1038/s41467-019-09114-z
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