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beta-Secretase cleavage is not required for generation of the intracellular C-terminal domain of the amyloid precursor family of proteins

机译：淀粉样蛋白前体家族的胞内C端结构域的生成不需要β-分泌酶裂解

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The amyloid precursor family of proteins are of considerable interest, both because of their role in Alzheimer's disease pathogenesis and because of their normal physiological functions. In mammals, the amyloid precursor protein (APP) has two homologs, amyloid precursor-like protein (APLP) 1 and APLP2. All three proteins undergo ectodomain shedding and regulated intramembrane proteolysis, and important functions have been attributed to the full-length proteins, shed ectodomains, C-terminal fragments and intracellular domains (ICDs). One of the proteases that is known to cleave APP and that is essential for generation of the amyloid beta-protein is the beta-site APP-cleaving enzyme 1 (BACE1). Here, we investigated the effects of genetic manipulation of BACE1 on the processing of the APP family of proteins. BACE1 expression regulated the levels and species of full-length APLP1, APP and APLP2, of their shed ectodomains, and of their membrane-bound C-terminal fragments. In particular, APP processing appears to be tightly regulated, with changes in beta-cleaved APPs (APPsbeta) being compensated for by changes in alpha-cleaved APPs (APPsalpha). In contrast, the total levels of soluble cleaved APLP1 and APLP2 species were less tightly regulated, and fluctuated with BACE1 expression. Importantly, the production of ICDs for all three proteins was not decreased by loss of BACE1 activity. These results indicate that BACE1 is involved in regulating ectodomain shedding, maturation and trafficking of the APP family of proteins. Consequently, whereas inhibition of BACE1 is unlikely to adversely affect potential ICD-mediated signaling, it may alter other important facets of amyloid precursor-like protein/APP biology.
机译：淀粉样蛋白前体家族的蛋白质引起人们极大的兴趣，这既是因为它们在阿尔茨海默氏病发病机理中的作用，又因为它们的正常生理功能。在哺乳动物中，淀粉样前体蛋白（APP）具有两个同源物，淀粉样前体样蛋白（APLP）1和APLP2。这三种蛋白质均经历胞外域脱落和调节的膜内蛋白水解作用，重要的功能已归因于全长蛋白质，脱落的胞外域，C末端片段和细胞内域（ICD）。已知能裂解APP且对淀粉样β蛋白产生至关重要的蛋白酶之一是β位APP裂解酶1（BACE1）。在这里，我们调查了基因操纵的BACE1对APP家族的蛋白质加工的影响。 BACE1的表达调节全长APLP1，APP和APLP2，其脱落的胞外域以及其膜结合的C端片段的水平和种类。尤其是，APP的处理似乎受到严格的监管，β切割的APP（APPsbeta）的变化被alpha切割的APP（APPsalpha）的变化所补偿。相比之下，可溶性裂解的APLP1和APLP2种类的总水平受到较少的严格调节，并随BACE1表达而波动。重要的是，所有三种蛋白质的ICD的产生都不会因BACE1活性的丧失而降低。这些结果表明，BACE1参与调节APP家族蛋白的胞外域脱落，成熟和运输。因此，尽管BACE1的抑制不太可能对潜在的ICD介导的信号产生不利影响，但它可能会改变淀粉样前体样蛋白/ APP生物学的其他重要方面。

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