Aluminum-sensitive degradation of amyloid beta-protein(1-40) by murine and human intracellular enzymes
Aluminum-sensitive degradation of amyloid beta-protein(1-40) by murine and human intracellular enzymes
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DOI：
10.1016/s0892-0362(96)00084-0
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发表时间：
1996-11-01
影响因子：
2.9
通讯作者：
Kastin, AJ
中科院分区：
文献类型：
--
作者：
Banks, WA;Maness, LM;Kastin, AJ
淀粉样β蛋白（A β）和铝（Al）都与阿尔茨海默病有关。最近，已经发现A β由外周组织以及CNS产生，并且穿过并积聚在脑的血管床中，所述血管床包括血脑屏障（BBB）。这增加了血液传播A β可能是CNS内A β来源的可能性。Al已显示改变A β的结构和功能，抑制与A β的加工和降解相关的酶（金属蛋白酶）类别，并改变BBB对与A β大小相似的肽的渗透性。因此，Al可以通过改变BBB的渗透性或通过影响酶降解来改变血液传播的A β进入CNS。我们检查了铝对这两个参数的影响，发现即使在校正体内降解后，铝也没有改变BBB对I-125放射性标记的A β（I-A β）的渗透性。然而，Al确实增强了循环中I-A β的清除和降解，但在大脑中没有。清除率的改变可通过改变循环物质向大脑的呈递来间接影响循环物质的CNS蓄积。对小鼠和人红细胞（RBC）裂解物的细胞内酶活性的体外研究表明，Al可抑制I-A β的降解，其抑制机制与RBC裂解物和Al的浓度有关，并与Ca ~（2+）拮抗。高效液相色谱分析表明，Al主要通过抑制I-A β降解为肽中间体而起作用，而不诱导I-A β聚集。在这些研究的条件下。阿尔茨海默病患者和年龄和性别匹配的对照组红细胞对铝的敏感性无差异。铝改变A β降解的能力表明，这两种潜在的神经毒性物质可能在阿尔茨海默病等疾病中相互作用。版权所有（C）1996 Elsevier Science Inc.
Both amyloid beta protein (A beta) and aluminum (Al) have been implicated in Alzheimer's disease. Recently, A beta has been found to be produced by peripheral tissues as well as by the CNS and to cross and accumulate in the vascular bed of the brain, which comprises the blood-brain barrier (BBB). This raises the possibility that blood-borne A beta may be a source of A beta within the CNS. Al has been shown to alter the structure and function of A beta, to inhibit the class of enzymes (metalloproteases) associated with the processing and degradation of A beta, and to alter the permeability of the BBB to peptides of similar size to A beta. Therefore, Al could alter the access of blood-borne A beta to the CNS either by changing the permeability of the BBB or by affecting enzymatic degradation. We examined the effect of Al on both of these parameters and found that Al did not alter the permeability of the BBB to A beta radioactively labeled with I-125 (I-A beta) even after correction for in vivo degradation. However, Al did enhance clearance and degradation of I-A beta in the circulation but not in the brain. Alterations in clearance can indirectly affect the CNS accumulation of circulating substances by modifying their presentation to the brain. In vitro studies of intracellular enzymatic activity of lysates of mouse and human erythrocytes (RBC) showed that Al could inhibit degradation of I-A beta through a mechanism antagonized by calcium and dependent on the concentrations of RBC lysate and Al. Analysis by high performance liquid chromatography showed that Al acted primarily by inhibiting the initial degradation of I-A beta to a peptide intermediate without inducing the aggregation of I-A beta under the conditions of these studies. No difference was found in sensitivity to Al between RBCs from patients with Alzheimer's disease and age- and sex-matched controls. The ability of Al to alter the degradation of A beta suggests a way in which these two potentially neurotoxic substances might interact in conditions such as Alzheimer's disease. Copyright (C) 1996 Elsevier Science Inc.