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) 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) 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. 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.

中文翻译：

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MMP9 调节可改善阿尔茨海默病小鼠模型中的特定神经行为缺陷

基质金属肽酶 9 (MMP9) 与多种神经系统疾病有关，包括阿尔茨海默病 (AD)，其中大脑和脑血管系统中 MMP9 水平升高。此前，我们的团队证明载脂蛋白 E4 (apoE4) 在调节大脑中 MMP9 活性方面​​比其他 apoE 亚型效率较低，并且 MMP9 抑制促进了 β-淀粉样蛋白 (Aβ) 穿过血脑屏障 (BBB) 的消除。我们使用两种方法评估了 MMP9 调节对 AD 中 Aβ 分布和神经行为的影响，(1) 在 apoE4 x AD (E4FAD) 小鼠中用 SB-3CT 对 MMP9 进行药理学抑制，以及 (2) AD 小鼠中 MMP9 基因删除。 MMP9KO/5xFAD) 与使用高架十字迷宫的安慰剂相比，用 MMP9 抑制剂 SB-3CT 治疗 E4FAD 小鼠可减少焦虑。通过三室任务评估，删除 5xFAD 小鼠中的 MMP9 基因还可以通过旷场测试减少焦虑，此外还可以改善社交能力和社会识别记忆，特别是在雄性小鼠中，这表明 AD 中的某些行为改变可能是介导的通过MMP9。然而，通过放射臂水迷宫测定，MMP9 的药理学抑制或 MMP9 的基因删除均不影响 AD 动物的空间学习或记忆。此外，MMP9 调节对 AD 神经行为的影响并不是由于 Aβ 分布的变化，因为与各自的对照组相比，SB-3CT 治疗的 E4FAD 动物和 MMP9KO/AD 小鼠的大脑和血浆 Aβ 水平没有变化。总的来说，虽然 MMP9 抑制确实改善了与 AD 相关的特定神经行为缺陷，例如焦虑和社会认知记忆，但 MMP9 的调节并没有改变 AD 动物的空间学习和记忆或 Aβ 组织水平。虽然靶向 MMP9 可能是减轻 AD 神经行为衰退方面的治疗策略，但还需要进一步的工作来了解 MMP9 活性与神经功能障碍之间关系的本质。