Protein expression of BACE1, BACE2 and APP in down syndrome brains
Protein expression of BACE1, BACE2 and APP in down syndrome brains
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DOI：
10.1007/s00726-007-0618-9
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发表时间：
2008-08-01
期刊：
影响因子：
3.5
通讯作者：
Lubec, G.
中科院分区：
文献类型：
--
作者：
Cheon, M. S.;Dierssen, M.;Lubec, G.
唐氏综合征（DS）是最常见的人类染色体异常，由21号染色体的额外拷贝引起。DS的表型被认为是由位于三重染色体或染色体区域上的一个或多个基因的过表达引起的。一些报告表明，DS的神经病理学包括发育异常和阿尔茨海默病样病变，如老年斑。老年斑的关键成分是淀粉样β肽，其通过β-分泌酶（BACE 1和BACE 2）和γ-分泌酶的顺序作用由淀粉样前体蛋白（APP）产生。BACE 1定位于11号染色体，APP和BACE 2位于21号染色体。为了挑战基因剂量效应并深入了解DS脑中β-分泌酶和APP之间的表达关系，我们评估了与对照相比，胎儿和成人DS脑中BACE 1、BACE 2和APP的蛋白表达水平。在胎仔脑中，DS组和对照组的BACE 2和APP蛋白表达水平相当。BACE 1升高，但未达到统计学显著性。在成人脑中，BACE 1和BACE 2在DS和对照组之间相当，但APP显著增加。我们得出结论，APP过度表达似乎是缺席的DS脑发育到18-19周的胎龄。然而，它在成年DS脑中的过度表达可能导致APP的正常功能紊乱，从而导致神经退行性变。BACE 1和BACE 2的相似表达反驳了β-分泌酶增加导致（甚至是导致）淀粉样蛋白A β片段产生增加的假设。
Down syndrome (DS) is the most common human chromosomal abnormality caused by an extra copy of chromosome 21. The phenotype of DS is thought to result from overexpression of a gene or genes located on the triplicated chromosome or chromosome region. Several reports have shown that the neuropathology of DS comprises developmental abnormalities and Alzheimer-like lesions such as senile plaques. A key component of senile plaques is amyloid beta-peptide which is generated from the amyloid precursor protein (APP) by sequential action of beta-secretases (BACE1 and BACE2) and gamma-secretase. While BACE1 maps to chromosome 11, APP and BACE2 are located on chromosome 21. To challenge the gene dosage effect and gain insight into the expressional relation between beta-secretases and APP in DS brain, we evaluated protein expression levels of BACE1, BACE2 and APP in fetal and adult DS brain compared to controls. In fetal brain, protein expression levels of BACE2 and APP were comparable between DS and controls. BACE1 was increased, but did not reach statistical significance. In adult brain, BACE1 and BACE2 were comparable between DS and controls, but APP was significantly increased. We conclude that APP overexpression seems to be absent during the development of DS brain up to 18-19 weeks of gestational age. However, its overexpression in adult DS brain could lead to disturbance of normal function of APP contributing to neurodegeneration. Comparable expression of BACE1 and BACE2 speaks against the hypothesis that increased beta-secretase results in (or even underlies) increased production of amyloidogenic A beta fragments.Furthermore, current data indicate that the DS phenotype cannot be fully explained by simple gene dosage effect.