MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease
Abstract 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 r...
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| Format: | Article |
| Language: | English |
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BMC
2021-05-01
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| Series: | BMC Neuroscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12868-021-00643-2 |
| _version_ | 1818833099432132608 |
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| author | Charis Ringland Jonas Elias Schweig Maxwell Eisenbaum Daniel Paris Ghania Ait-Ghezala Michael Mullan Fiona Crawford Laila Abdullah Corbin Bachmeier |
| author_facet | Charis Ringland Jonas Elias Schweig Maxwell Eisenbaum Daniel Paris Ghania Ait-Ghezala Michael Mullan Fiona Crawford Laila Abdullah Corbin Bachmeier |
| author_sort | Charis Ringland |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T02:13:32Z |
| format | Article |
| id | doaj.art-98c517197d3249dfb8bb42660dcb0256 |
| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-12-19T02:13:32Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj.art-98c517197d3249dfb8bb42660dcb02562022-12-21T20:40:33ZengBMCBMC Neuroscience1471-22022021-05-0122112510.1186/s12868-021-00643-2MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s diseaseCharis Ringland0Jonas Elias Schweig1Maxwell Eisenbaum2Daniel Paris3Ghania Ait-Ghezala4Michael Mullan5Fiona Crawford6Laila Abdullah7Corbin Bachmeier8The Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteThe Roskamp InstituteAbstract 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.https://doi.org/10.1186/s12868-021-00643-2Alzheimer’s diseaseMatrix metallopeptidase 9Apolipoprotein ESocial recognition memoryBeta-amyloid |
| spellingShingle | Charis Ringland Jonas Elias Schweig Maxwell Eisenbaum Daniel Paris Ghania Ait-Ghezala Michael Mullan Fiona Crawford Laila Abdullah Corbin Bachmeier MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease BMC Neuroscience Alzheimer’s disease Matrix metallopeptidase 9 Apolipoprotein E Social recognition memory Beta-amyloid |
| 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 | Alzheimer’s disease Matrix metallopeptidase 9 Apolipoprotein E Social recognition memory Beta-amyloid |
| url | https://doi.org/10.1186/s12868-021-00643-2 |
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