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Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease

Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress,...

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Autores principales: Shi, Yongchuan, Lv, Jinpeng, Chen, Ling, Luo, Guojun, Tao, Mengjia, Pan, Jianchun, Hu, Xiaoxiong, Sheng, Jianwen, Zhang, Shanjin, Zhou, Min, Fan, Huizhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446525/
https://www.ncbi.nlm.nih.gov/pubmed/34539384
http://dx.doi.org/10.3389/fnagi.2021.722580
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author Shi, Yongchuan
Lv, Jinpeng
Chen, Ling
Luo, Guojun
Tao, Mengjia
Pan, Jianchun
Hu, Xiaoxiong
Sheng, Jianwen
Zhang, Shanjin
Zhou, Min
Fan, Huizhen
author_facet Shi, Yongchuan
Lv, Jinpeng
Chen, Ling
Luo, Guojun
Tao, Mengjia
Pan, Jianchun
Hu, Xiaoxiong
Sheng, Jianwen
Zhang, Shanjin
Zhou, Min
Fan, Huizhen
author_sort Shi, Yongchuan
collection PubMed
description Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.
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spelling pubmed-84465252021-09-18 Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease Shi, Yongchuan Lv, Jinpeng Chen, Ling Luo, Guojun Tao, Mengjia Pan, Jianchun Hu, Xiaoxiong Sheng, Jianwen Zhang, Shanjin Zhou, Min Fan, Huizhen Front Aging Neurosci Neuroscience Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties. Frontiers Media S.A. 2021-09-03 /pmc/articles/PMC8446525/ /pubmed/34539384 http://dx.doi.org/10.3389/fnagi.2021.722580 Text en Copyright © 2021 Shi, Lv, Chen, Luo, Tao, Pan, Hu, Sheng, Zhang, Zhou and Fan. 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
Shi, Yongchuan
Lv, Jinpeng
Chen, Ling
Luo, Guojun
Tao, Mengjia
Pan, Jianchun
Hu, Xiaoxiong
Sheng, Jianwen
Zhang, Shanjin
Zhou, Min
Fan, Huizhen
Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title_full Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title_fullStr Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title_full_unstemmed Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title_short Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease
title_sort phosphodiesterase-4d knockdown in the prefrontal cortex alleviates memory deficits and synaptic failure in mouse model of alzheimer’s disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446525/
https://www.ncbi.nlm.nih.gov/pubmed/34539384
http://dx.doi.org/10.3389/fnagi.2021.722580
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