Altered amyloid-β metabolism and deposition in genomic-based β-secretase transgenic mice
Altered amyloid-β metabolism and deposition in genomic-based β-secretase transgenic mice
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DOI：
10.1074/jbc.m409680200
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发表时间：
2004-12-10
影响因子：
4.8
通讯作者：
Lamb, BT
中科院分区：
文献类型：
--
作者：
Chiocco, MJ;Kulnane, LS;Lamb, BT
淀粉样β蛋白(Abeta)是阿尔茨海默病(AD)中发现的老年斑的主要成分，由β-分泌酶对淀粉样前体蛋白(APP)的限速裂解以及随后的伽马-分泌酶裂解而产生。主要的β-分泌酶基因BACE1的鉴定为研究这种独特的天冬氨酸蛋白酶在改变AD中发生的Abeta代谢和沉积中所起的作用提供了一个独特的机会。目前的实验试图研究调节β-分泌酶的表达和活性如何改变体内的APP处理和Abeta代谢。建立了基于基因组的高表达人BACE1基因和蛋白的BACE1转基因小鼠。将表达水平最高的BACE1转基因品系与含有人APP转基因的转基因小鼠交配。我们的生化和组织化学研究表明，同时过度表达BACE1和APP的小鼠在APP处理和年龄相关的Abeta沉积方面显示出特定的变化。我们观察到，在这些双转基因动物中，Abeta亚型水平升高，Abeta沉积显著增加。特别是，双转基因动物表现出独特的皮质沉积特征，这与BACE1在大脑皮质相对于其他脑区的表达显著增加是一致的。BACE1表达的升高和沉积的增加为β-分泌酶在AD脑内局部淀粉样蛋白沉积中的主要效应提供了功能证据。我们的研究首次证明，BACE1活性的调节可能在体内AD的发病机制中发挥重要作用。
Amyloid-beta (Abeta) the primary component of the senile plaques found in Alzheimer's disease ( AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase cleavage. Identification of the primary beta-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Abeta metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating beta-secretase expression and activity alters APP processing and Abeta metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent Abeta deposition. We observed elevated levels of Abeta isoforms as well as significant increases of Abeta deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo.