Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils
Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils
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DOI：
10.1091/mbc.e06-10-0975
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发表时间：
2007-04-01
影响因子：
3.3
通讯作者：
Maxfield, Frederick R.
中科院分区：
文献类型：
--
作者：
Majumdar, Amitabha;Cruz, Dana;Maxfield, Frederick R.
小胶质细胞是大脑的主要免疫细胞，在某些情况下，它们可以在去除纤维状阿尔茨海默氏淀粉样蛋白13肽（fA β）中发挥重要作用。原代小鼠小胶质细胞可以内化fA β，但不能有效降解。我们比较了小胶质细胞和J774巨噬细胞中溶酶体蛋白酶的水平，它们可以有效地降解fA β，我们发现小胶质细胞实际上比巨噬细胞含有更高水平的许多溶酶体蛋白酶。然而，小胶质细胞溶酶体的酸性较低（平均pH值接近6），降低了细胞中溶酶体酶的活性。巨噬细胞集落刺激因子（MCSF）或白细胞介素-6的促炎治疗酸化小胶质细胞的溶酶体，使它们能够降解fA β。用MCSF处理后，小胶质细胞溶酶体的pH值与J774巨噬细胞相似（pH值与5相似），用蛋白激酶A抑制剂或阴离子转运抑制剂处理后，MCSF诱导的酸化可部分逆转。如果溶酶体被氨脉冲洗涤或用毛喉素处理酸化，小胶质细胞也会降解fA β，毛喉素激活蛋白激酶A。我们的研究结果表明，受调节的溶酶体酸化可以增强小胶质细胞对fA β的降解。
Microglia are the main immune cells of the brain, and under some circumstances they can play an important role in removal of fibrillar Alzheimer amyloid 13 peptide (fA beta). Primary mouse microglia can internalize fA beta, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fA beta efficiently, and we found that microglia actually contain higher levels of many lysosomal proteases than macrophages. However, the microglial lysosomes are less acidic (average pH of similar to 6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with macrophage colony-stimulating factor (MCSF) or interleukin-6 acidify the lysosomes of microglia and enable them to degrade fA beta. After treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH of similar to 5), and the MCSF-induced acidification can be partially reversed upon treatment with an inhibitor of protein kinase A or with an anion transport inhibitor. Microglia also degrade fA beta if lysosomes are acidified by an ammonia pulse-wash or by treatment with forskolin, which activates protein kinase A. Our results indicate that regulated lysosomal acidification can potentiate fA beta degradation by microglia.