NOVEL PRECURSOR OF ALZHEIMERS-DISEASE AMYLOID PROTEIN SHOWS PROTEASE INHIBITORY ACTIVITY
NOVEL PRECURSOR OF ALZHEIMERS-DISEASE AMYLOID PROTEIN SHOWS PROTEASE INHIBITORY ACTIVITY
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DOI：
10.1038/331530a0
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发表时间：
1988-02-11
期刊：
影响因子：
64.8
通讯作者：
ITO, H
中科院分区：
文献类型：
--
作者：
KITAGUCHI, N;TAKAHASHI, Y;ITO, H
阿尔茨海默病1的特征在于作为老年斑核心和血管淀粉样蛋白2 -6的淀粉样β蛋白（AP）的脑沉积，并且已经从人脑中克隆了编码该蛋白（APP）前体的互补DNA 7 -11。从人胶质母细胞瘤细胞系的cDNA文库中，我们已经分离出与先前报道的相同的cDNA，以及含有225个核苷酸插入的新cDNA。从该插入片段推导的蛋白质N-末端的56个氨基酸的序列与碱性胰蛋白酶抑制剂家族高度同源12，并且用较长的APP cDNA转染的COS-1细胞的裂解物显示出对胰蛋白酶活性的增加的抑制。对APP基因组DNA的部分测序结果表明，APP基因的225个核苷酸分别位于两个外显子上。在人脑中至少发现了三种信使RNA，它们显然是由单个APP基因通过选择性剪接转录而来的。我们认为较长APP对蛋白酶的抑制可能与异常APP催化有关。
Alzheimer's disease1is characterized by cerebral deposits of amyloidβ-protein (AP) as senile plaque core and vascular amyloid2–6, and a complementary DNA encoding a precursor of this protein (APP) has been cloned from human brain7–11. From a cDNA library of a human glioblastoma cell line, we have isolated a cDNA identical to that previously reported, together with a new cDNA which contains a 225-nucleotide insert. The sequence of the 56 a mi no acids at the N-terminal of the protein deduced from this insert is highly homologous to the basic trypsin inhibitor family12, and the lysate from COS-1 cells transfected with the longer APP cDNA showed an increased inhibition of trypsin activity. Partial sequencing of the genomic DNA encoding APP showed that the 225 nucleotides are located in two exons. At least three messenger RNA species, apparently transcribed from a single APP gene by alternative splicing, were found in human brain. We suggest that protease inhibition by the longer APP(s) could be related to aberrant APP catabolism.