Mentlein R, Ludwig R, Martensen I
Anatomisches Institut, Universität Kiel, Germany.
J Neurochem. 1998 Feb;70(2):721-6. doi: 10.1046/j.1471-4159.1998.70020721.x.
The cerebral deposition of amyloid beta-peptide (A beta) is a histopathological characteristic of Alzheimer's disease. Because an impaired clearance of A beta might be involved in the disease, we investigated the proteolytic degradation of synthetic A beta (40-residue peptide) in cultures of glial cells and characterized a protease involved. Whereas rat astrocytes had a very low degradation capacity, cultivated rat microglia cells cleaved A beta. Microglia activity was considerably enhanced by stimulation with lipopolysaccharide and to a lesser extent by phorbol esters. Most of the A beta-degrading activity was released into the medium. By use of selective inhibitors the protease was characterized as a metalloprotease of approximately 200 kDa that was different from neutral endopeptidase (a neuropeptide-degrading enzyme), matrix metalloproteases, or macrophage elastase. Its activity was efficiently reduced by four hydroxamic acid-based zinc-metalloprotease inhibitors that have been shown to inhibit membrane protein secretases (disintegrins). We conclude that activated microglia cells might impair amyloid plaque formation by release of a metalloprotease that degrades soluble A beta, before polymerization.
淀粉样β肽（Aβ）在大脑中的沉积是阿尔茨海默病的组织病理学特征。由于Aβ清除受损可能与该病有关，我们研究了胶质细胞培养物中合成Aβ（40个氨基酸残基的肽）的蛋白水解降解，并对其中涉及的一种蛋白酶进行了表征。大鼠星形胶质细胞的降解能力很低，而培养的大鼠小胶质细胞能够切割Aβ。脂多糖刺激可显著增强小胶质细胞的活性，佛波酯刺激则在较小程度上增强其活性。大部分Aβ降解活性释放到培养基中。通过使用选择性抑制剂，该蛋白酶被表征为一种约200 kDa的金属蛋白酶，它不同于中性内肽酶（一种神经肽降解酶）、基质金属蛋白酶或巨噬细胞弹性蛋白酶。四种基于异羟肟酸的锌金属蛋白酶抑制剂可有效降低其活性，这些抑制剂已被证明可抑制膜蛋白分泌酶（解整合素）。我们得出结论，活化的小胶质细胞可能通过释放一种金属蛋白酶来损害淀粉样斑块的形成，该金属蛋白酶在聚合之前降解可溶性Aβ。
