MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer\u2019s disease

Charis Ringland,Ghania Ait-Ghezala,Daniel Paris,Fiona Crawford,Jonas Elias Schweig,Michael Mullan,Corbin Bachmeier,Maxwell Eisenbaum,Laila Abdullah

doi:10.1186/s12868-021-00643-2

Charis Ringland, Ghania Ait-Ghezala + Show 7 more

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https://doi.org/10.1186/s12868-021-00643-2

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Abstract

BackgroundMatrix 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)MethodsIn 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)ResultsTreatment 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.ConclusionsIn 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.

Highlights

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
Pharmacological inhibition of MMP9 activity with SB‐3CT in E4FAD mice SB‐3CT treatment influenced anxiety levels but not motor activity in E4FAD mice Following 2 weeks of daily SB-3CT injections, the elevated plus maze (EPM) and the open field test (OFT) revealed no differences in total distance travelled or average velocity between the SB-3CT-treated and vehicle-treated mice (Fig. 2b, c, e, f ), indicating the drug treatment does not alter locomotor activity
SB‐3CT treatment did not impact social interaction, social memory, or spatial memory E4FAD mice treated with either SB-3CT or vehicle showed no preference for the chamber or proximal zone containing a mouse compared to an empty cage in the three-chamber test (Fig. 3a, b)

Summary

Introduction

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. MMP9 has been implicated in a variety of neurological and inflammatory disease states and elevated MMP9 levels have been reported in cerebrovascular disorders such as Alzheimer’s disease (AD) [1,2,3], cerebral amyloid angiopathy [4], ischemia [5, 6], and intracerebral hemorrhage [7]. With respect to AD, studies have shown that MMP9 brain levels were elevated in patients with moderate and late AD [8] and MMP9 levels in cerebrospinal fluid (CSF) were associated with faster decline in an MCI to AD conversion group [9]. The Aβ-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout (KO) mice and treatment with MMP inhibitors [10]

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