Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways
As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates si...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611930292X |
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doaj-0555bcd7882b4d0fb94610581f5138af |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Zhiyun Wei Xingjun Meng Rachid El Fatimy Bowen Sun Dongmei Mai Junfang Zhang Ramil Arora Ailiang Zeng Pingyi Xu Shaogang Qu Anna M. Krichevsky Dennis J. Selkoe Shaomin Li |
| spellingShingle |
Zhiyun Wei Xingjun Meng Rachid El Fatimy Bowen Sun Dongmei Mai Junfang Zhang Ramil Arora Ailiang Zeng Pingyi Xu Shaogang Qu Anna M. Krichevsky Dennis J. Selkoe Shaomin Li Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways Neurobiology of Disease |
| author_facet |
Zhiyun Wei Xingjun Meng Rachid El Fatimy Bowen Sun Dongmei Mai Junfang Zhang Ramil Arora Ailiang Zeng Pingyi Xu Shaogang Qu Anna M. Krichevsky Dennis J. Selkoe Shaomin Li |
| author_sort |
Zhiyun Wei |
| title |
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| title_short |
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| title_full |
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| title_fullStr |
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| title_full_unstemmed |
Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| title_sort |
environmental enrichment prevents aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2020-02-01 |
| description |
As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging. |
| url |
http://www.sciencedirect.com/science/article/pii/S096999611930292X |
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doaj-0555bcd7882b4d0fb94610581f5138af2021-03-22T12:48:43ZengElsevierNeurobiology of Disease1095-953X2020-02-01134Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathwaysZhiyun Wei0Xingjun Meng1Rachid El Fatimy2Bowen Sun3Dongmei Mai4Junfang Zhang5Ramil Arora6Ailiang Zeng7Pingyi Xu8Shaogang Qu9Anna M. Krichevsky10Dennis J. Selkoe11Shaomin Li12Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, ChinaCentral Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, ChinaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaCentral Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, ChinaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, HMS Initiative for RNA Medicine, Zhejiang, ChinaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaDepartment of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaCentral Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, ChinaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of AmericaAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Corresponding author at: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115, United States of America.As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.http://www.sciencedirect.com/science/article/pii/S096999611930292X |