Endres Kristina, Postina Rolf, Schroeder Anja, Mueller Ulrike, Fahrenholz Falk
Institute of Biochemistry, Johannes Gutenberg-University Mainz, Germany.
FEBS J. 2005 Nov;272(22):5808-20. doi: 10.1111/j.1742-4658.2005.04976.x.
Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence by the alpha-secretase prevents the formation of toxic Abeta peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act as alpha-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsalpha. Here we demonstrate that the related APP-like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10-preferring inhibitor. Transgenic mice with neuron-specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C-terminal fragments. To elucidate a possible regulatory mechanism of APLP2 shedding in the neuronal context, we examined retinoic acid-induced differentiation of neuroblastoma cells. Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2.
α-分泌酶在淀粉样β蛋白（Aβ）序列内切割淀粉样前体蛋白（APP）可防止有毒Aβ肽的形成。研究表明，解整合素-金属蛋白酶ADAM10和肿瘤坏死因子-α转换酶（TACE，即ADAM17）可作为α-分泌酶，并刺激生成APP的可溶性神经保护片段APPsα。在此我们证明，已显示对小鼠发育和存活至关重要的相关类APP蛋白2（APLP2）也是这两种蛋白酶的底物。在HEK293细胞中过表达ADAM10或TACE可使神经营养性可溶性APLP2的释放增加数倍。使用一种更偏向ADAM10的抑制剂可观察到对神经母细胞瘤细胞中APLP2脱落的最强抑制作用。神经元特异性过表达ADAM10的转基因小鼠显示可溶性APLP2及其C末端片段的水平显著增加。为阐明神经细胞环境中APLP2脱落的可能调控机制，我们检测了视黄酸诱导的神经母细胞瘤细胞分化。用视黄酸处理两种神经母细胞瘤细胞系可上调APLP2和ADAM10的表达，从而导致可溶性APLP2的释放增加。
