Apolipoprotein E (APOE) has been shown to influence amyloid-β (Aβ) clearance from the brain in an isoform-specific manner. Our prior work showed that Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia. Recently, we demonstrated that matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain. The current studies interrogated the relationship between apoE and MMP-9 and found that apoE impacted proMMP-9 cellular secretion from brain endothelia (apoE2 < apoE3 = apoE4). In a cell-free assay, apoE dose-dependently reduced MMP-9 activity, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3. Finally, we observed elevated MMP-9 expression and activity in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype. Collectively, these findings suggest a role for apoE in regulating MMP-9 disposition and may describe the effect of apoE4 on Aβ pathology in the AD brain.

中文翻译：

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载脂蛋白 E 亚型差异调节阿尔茨海默病中的基质金属肽酶 9 功能

载脂蛋白 E (APOE) 已被证明以亚型特异性方式影响大脑中淀粉样蛋白 β (Aβ) 的清除。我们之前的工作表明，与其他 apoE 同种型相比，apoE4 减少了 Aβ 通过血脑屏障的转运，这是由于脑内皮细胞中脂蛋白受体脱落升高。最近，我们证明基质金属肽酶 9 (MMP-9) 以 apoE 异构体依赖性方式诱导脂蛋白受体蛋白水解，这会影响 Aβ 从大脑中的消除。目前的研究询问了 apoE 和 MMP-9 之间的关系，发现 apoE 影响了脑内皮细胞分泌 proMMP-9（apoE2 < apoE3 = apoE4）。在无细胞试验中，apoE 剂量依赖性地降低 MMP-9 活性，apoE4 显示出比 apoE2 或 apoE3 显着弱于抑制 MMP-9 功能的能力。最后，我们在具有 APOE4 基因型的人和动物 AD 脑标本的脑血管系统中观察到 MMP-9 表达和活性升高。总的来说，这些发现表明 apoE 在调节 MMP-9 配置中的作用，并且可能描述了 apoE4 对 AD 脑中 Aβ 病理的影响。