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MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

BACKGROUND: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulatin...

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Autores principales: Ringland, Charis, Schweig, Jonas Elias, Eisenbaum, Maxwell, Paris, Daniel, Ait-Ghezala, Ghania, Mullan, Michael, Crawford, Fiona, Abdullah, Laila, Bachmeier, Corbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152085/
https://www.ncbi.nlm.nih.gov/pubmed/34034683
http://dx.doi.org/10.1186/s12868-021-00643-2
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author Ringland, Charis
Schweig, Jonas Elias
Eisenbaum, Maxwell
Paris, Daniel
Ait-Ghezala, Ghania
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
Bachmeier, Corbin
author_facet Ringland, Charis
Schweig, Jonas Elias
Eisenbaum, Maxwell
Paris, Daniel
Ait-Ghezala, Ghania
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
Bachmeier, Corbin
author_sort Ringland, Charis
collection PubMed
description BACKGROUND: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB) METHODS: In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) RESULTS: Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. CONCLUSIONS: In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12868-021-00643-2.
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spelling pubmed-81520852021-05-26 MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease Ringland, Charis Schweig, Jonas Elias Eisenbaum, Maxwell Paris, Daniel Ait-Ghezala, Ghania Mullan, Michael Crawford, Fiona Abdullah, Laila Bachmeier, Corbin BMC Neurosci Research BACKGROUND: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB) METHODS: In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) RESULTS: Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. CONCLUSIONS: In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12868-021-00643-2. BioMed Central 2021-05-25 /pmc/articles/PMC8152085/ /pubmed/34034683 http://dx.doi.org/10.1186/s12868-021-00643-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ringland, Charis
Schweig, Jonas Elias
Eisenbaum, Maxwell
Paris, Daniel
Ait-Ghezala, Ghania
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
Bachmeier, Corbin
MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title_full MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title_fullStr MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title_full_unstemmed MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title_short MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
title_sort mmp9 modulation improves specific neurobehavioral deficits in a mouse model of alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152085/
https://www.ncbi.nlm.nih.gov/pubmed/34034683
http://dx.doi.org/10.1186/s12868-021-00643-2
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