Degradation of fibrillar forms of Alzheimer's amyloid β-peptide by macrophages
Degradation of fibrillar forms of Alzheimer's amyloid β-peptide by macrophages
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DOI：
10.1016/j.neurobiolaging.2006.12.001
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发表时间：
2008-05-01
影响因子：
4.2
通讯作者：
Maxfield, Frederick R.
中科院分区：
文献类型：
--
作者：
Majumdar, Amitabha;Chung, Haeyong;Maxfield, Frederick R.
培养的小胶质细胞内化纤维淀粉样蛋白Aβ(FAβ)，并将其传递给溶酶体。小胶质细胞对FAβ的降解是不完全的，而巨噬细胞对FAβ的降解是有效的。在小胶质细胞的培养液中加入甘露糖-6磷酸化溶酶体酶后，FAβ的降解增加，而过量的甘露糖-6-磷酸抑制了这种增加的降解，从而竞争结合和内吞摄取。这表明，小胶质细胞中一种或多种溶酶体酶的活性低是导致FAβ降解不良的原因。为了进一步表征FAβ在晚期内体和溶酶体中的降解情况，我们用质谱仪分析了FAβ在巨噬细胞和小胶质细胞中的细胞内降解产物。在两种细胞的提取液中都观察到了前12个N末端残基被截断的片段。我们还分析了细胞释放的物质。小胶质细胞主要释放完整的AβI-42，而巨噬细胞释放各种N末端截短的片段。这些结果表明，在两种细胞类型中，N端附近的初始蛋白分解是相似的，但小胶质细胞在进一步切割FAβ的能力方面是有限的。(C)2007 Elsevier Inc.保留所有权利。
Cultured microglia internalize fibrillar amyloid A beta (fA beta) and deliver it to lysosomes. Degradation of fA beta by microglia is incomplete, but macrophages degrade fA beta efficiently. When mannose-6 phosphorylated lysosomal enzymes were added to the culture medium of microglia, degradation of fA beta was increased, and the increased degradation was inhibited by excess mannose-6-phosphate, which competes for binding and endocytic uptake. This suggests that low activity of one or more lysosomal enzymes in the microglia was responsible for the poor degradation of fA beta. To further characterize the degradation of fA beta in late endosomes and lysosomes, we analyzed fA beta-derived intracellular degradation products in macrophages and microglia by mass spectrometry. Fragments with truncations in the first 12 N-terminal residues were observed in extracts from both cell types. We also analyzed material released by the cells. Microglia released mainly intact A beta I-42, whereas macrophages released a variety of N-terminal truncated fragments. These results indicate that initial proteolysis near the N-terminus is similar in both cell types, but microglia are limited in their ability to make further cuts in the fA beta. (c) 2007 Elsevier Inc. All rights reserved.