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Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetyl...

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Autores principales: O'Connor, Margaret, Shentu, Yang-Ping, Wang, Guan, Hu, Wen-Ting, Xu, Zhen-Dong, Wang, Xiao-Chuan, Liu, Rong, Man, Heng-Ye
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476873/
https://www.ncbi.nlm.nih.gov/pubmed/32861999
http://dx.doi.org/10.1016/j.isci.2020.101465
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author O'Connor, Margaret
Shentu, Yang-Ping
Wang, Guan
Hu, Wen-Ting
Xu, Zhen-Dong
Wang, Xiao-Chuan
Liu, Rong
Man, Heng-Ye
author_facet O'Connor, Margaret
Shentu, Yang-Ping
Wang, Guan
Hu, Wen-Ting
Xu, Zhen-Dong
Wang, Xiao-Chuan
Liu, Rong
Man, Heng-Ye
author_sort O'Connor, Margaret
collection PubMed
description In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.
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spelling pubmed-74768732020-09-15 Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease O'Connor, Margaret Shentu, Yang-Ping Wang, Guan Hu, Wen-Ting Xu, Zhen-Dong Wang, Xiao-Chuan Liu, Rong Man, Heng-Ye iScience Article In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aβ incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aβ-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aβ-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics. Elsevier 2020-08-15 /pmc/articles/PMC7476873/ /pubmed/32861999 http://dx.doi.org/10.1016/j.isci.2020.101465 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
O'Connor, Margaret
Shentu, Yang-Ping
Wang, Guan
Hu, Wen-Ting
Xu, Zhen-Dong
Wang, Xiao-Chuan
Liu, Rong
Man, Heng-Ye
Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title_full Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title_fullStr Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title_full_unstemmed Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title_short Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease
title_sort acetylation of ampa receptors regulates receptor trafficking and rescues memory deficits in alzheimer's disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476873/
https://www.ncbi.nlm.nih.gov/pubmed/32861999
http://dx.doi.org/10.1016/j.isci.2020.101465
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