Lefterov I M, Koldamova R P, Lazo J S
Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
FASEB J. 2000 Sep;14(12):1837-47. doi: 10.1096/fj.99-0938com.
Human bleomycin hydrolase (hBH) is a neutral cysteine protease genetically associated with increased risk for Alzheimer disease. We show here that ectopic expression of hBH in 293APPwt and CHOAPPsw cells altered the processing of amyloid precursor protein (APP) and increased significantly the release of its proteolytic fragment, beta amyloid (Abeta). We also found that hBH interacted and colocalized with APP as determined by subcellular fractionation, in vitro binding assay, and confocal immunolocalization. Metabolic labeling and pulse-chase experiments showed that ectopic hBH expression increased secretion of soluble APPalpha/beta products without changing the half-life of cellular APP. We also observed that this increased Abeta secretion was independent of hBH isoforms. Our findings suggest a regulatory role for hBH in APP processing pathways.
人博来霉素水解酶（hBH）是一种中性半胱氨酸蛋白酶，在基因上与患阿尔茨海默病的风险增加相关。我们在此表明，hBH在293APPwt和CHOAPPsw细胞中的异位表达改变了淀粉样前体蛋白（APP）的加工过程，并显著增加了其蛋白水解片段β淀粉样蛋白（Aβ）的释放。我们还发现，通过亚细胞分级分离、体外结合测定和共聚焦免疫定位确定，hBH与APP相互作用并共定位。代谢标记和脉冲追踪实验表明，hBH的异位表达增加了可溶性APPα/β产物的分泌，而不改变细胞APP的半衰期。我们还观察到，这种Aβ分泌的增加与hBH同工型无关。我们的研究结果表明hBH在APP加工途径中具有调节作用。
