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Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model. Methods: Bilateral ovariectomy was conducted...

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Autores principales: Zhao, Wei, Hou, Yue, Song, Xinxin, Wang, Lei, Zhang, Fangfang, Zhang, Hanting, Yu, Haiyang, Zhou, Yanmeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319728/
https://www.ncbi.nlm.nih.gov/pubmed/34335235
http://dx.doi.org/10.3389/fnagi.2021.713819
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author Zhao, Wei
Hou, Yue
Song, Xinxin
Wang, Lei
Zhang, Fangfang
Zhang, Hanting
Yu, Haiyang
Zhou, Yanmeng
author_facet Zhao, Wei
Hou, Yue
Song, Xinxin
Wang, Lei
Zhang, Fangfang
Zhang, Hanting
Yu, Haiyang
Zhou, Yanmeng
author_sort Zhao, Wei
collection PubMed
description Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model. Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls. Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced. Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency.
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spelling pubmed-83197282021-07-30 Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model Zhao, Wei Hou, Yue Song, Xinxin Wang, Lei Zhang, Fangfang Zhang, Hanting Yu, Haiyang Zhou, Yanmeng Front Aging Neurosci Neuroscience Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model. Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls. Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced. Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency. Frontiers Media S.A. 2021-07-15 /pmc/articles/PMC8319728/ /pubmed/34335235 http://dx.doi.org/10.3389/fnagi.2021.713819 Text en Copyright © 2021 Zhao, Hou, Song, Wang, Zhang, Zhang, Yu and Zhou. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Zhao, Wei
Hou, Yue
Song, Xinxin
Wang, Lei
Zhang, Fangfang
Zhang, Hanting
Yu, Haiyang
Zhou, Yanmeng
Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title_full Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title_fullStr Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title_full_unstemmed Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title_short Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
title_sort estrogen deficiency induces mitochondrial damage prior to emergence of cognitive deficits in a postmenopausal mouse model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319728/
https://www.ncbi.nlm.nih.gov/pubmed/34335235
http://dx.doi.org/10.3389/fnagi.2021.713819
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