Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism
Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism
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DOI：
10.1523/jneurosci.5302-08.2009
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发表时间：
2009-03-18
影响因子：
5.3
通讯作者：
Paul, Steven M.
中科院分区：
文献类型：
--
作者：
Zhao, Lingzhi;Lin, Suizhen;Paul, Steven M.
最近的研究表明，骨髓源性巨噬细胞可以有效地减少β-淀粉样蛋白（A β）在脑中的沉积。为了进一步阐明巨噬细胞降解A β的机制，我们在来自表达PDAPP [具有由血小板衍生生长因子启动子驱动的APP（717 V>F）突变的人淀粉样前体蛋白（APP）]的转基因小鼠的带有A β斑块的脑切片上培养鼠巨噬细胞。使用这种离体测定，我们发现来自野生型小鼠的巨噬细胞以时间依赖性方式非常有效地降解可溶性和不溶性A β，并显著消除硫代嘌呤-S阳性淀粉样蛋白沉积物。由于巨噬细胞表达和分泌载脂蛋白E（apoE），我们比较了从apoE缺陷小鼠或表达人apoE 2，apoE 3或apoE 4的小鼠制备的巨噬细胞A β降解的效率。表达apoE 2的巨噬细胞比表达apoE 3、表达apoE 4或apoE缺陷的巨噬细胞更有效地降解A β。此外，巨噬细胞诱导的A β降解被抗apoE抗体和受体相关蛋白（低密度脂蛋白（LDL）受体家族的拮抗剂）有效阻断，表明LDL受体参与。与含A β的脑切片共培养的表达apoE的人巨噬细胞的培养基中基质金属蛋白酶-9（MMP-9）活性的测量显示，表达apoE 2的巨噬细胞中MMP-9活性水平高于表达apoE 3或apoE 4的巨噬细胞。MMP-9活性的差异似乎有助于巨噬细胞A β降解的同种型特异性差异。巨噬细胞对A β降解的这些apoE亚型依赖性作用表明A β从脑中清除的一种新的“外周”机制，这也可以部分解释apoE在确定阿尔茨海默病遗传风险中的亚型依赖性作用。
Recent studies suggest that bone marrow-derived macrophages can effectively reduce beta-amyloid (A beta) deposition in brain. To further elucidate the mechanisms by which macrophages degrade A beta, we cultured murine macrophages on top of A beta plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP(717V>F) mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble A beta in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of A beta degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading A beta than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of A beta was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with A beta-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3-or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in A beta degradation by macrophages. These apoE isoform-dependent effects of macrophages on A beta degradation suggest a novel "peripheral" mechanism for A beta clearance from brain that may also, in part, explain the isoform-dependent effects of apoE in determining the genetic risk for Alzheimer's disease.