pp6068克隆蛋白与BACE1的相互作用
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摘要
阿尔茨海默氏病(Alzheimer's disease,AD)是一种以渐进性记忆力丧失和认知障碍为主要症状的神经退行性疾病,在患者脑部出现两个明显的病理组织学特征:即细胞内神经原纤维缠结(neurofibrillary tangle,NFT)和细胞外形成淀粉样斑(senile plaque,SP)。研究表明SPs中含有大量的β-淀粉样蛋白(beta-Amyloidprotein,Aβ),BACE1(β-site APP-cleaving enzyme;APP,amyloid precursor protein)被认为是Aβ形成的关键酶,已经成为目前阿尔茨海默症研究的热点之一。但目前对于BACE1的生理功能和作用机制仍然缺乏全面的了解。
为了更清楚地认识和了解BACE1在阿尔茨海默症发病过程中的作用,我们实验室以BACE1的胞内端第473位至第501位氨基酸构建诱饵蛋白,利用酵母双杂交的方法在人胎脑cDNA文库进行筛选,得到一个能与BACE1相互作用的蛋白:pp6068克隆蛋白。
我们构建了pp6068克隆蛋白在哺乳动物细胞中的稳定表达的载体,免疫共沉淀实验证明外源性的pp6068克隆蛋白和BACE1在HEK293T细胞中能够发生相互作用。在N2a/APP695细胞中,pp6068克隆蛋白的过表达能够上调BACE1的水解产物APP/βCTF和Aβ的蛋白水平,同时,还能够下调α-分泌酶的水解产物sAPPα的蛋白水平。
这些研究说明,pp6068克隆蛋白可能参与了BACE1活性的调节,影响APP的降解和Aβ的形成。同时也可能对α-分泌酶对APP的水解过程产生了影响。对于与BACE1相互作用的蛋白的研究不仅有利于揭示pp6068克隆蛋白在哺乳动物中的生物学功能,还可能为研究BACE1生理功能和AD的治疗开辟新的途径。
Alzheimer's disease(AD) is a neurodegenerative disorder which is characterized clinically by progressive loss of memory and impairment of cognitive abilities. Neurofibrillary tangle(NFT) and senile plaque(SP) are the two histological characters found in the brain of AD patients.Recent researches have showed that the major component of SPs is Aβ(β-amyloid peptides).BACE1(β-site APP cleaving enzyme;APP,amyloid precursor protein),identified as a key enzyme during the Aβformation,has become one of the hotspots of Alzheimer's disease research.However, some pathophysiological functions of BACE1 and the underlying mechanisms still remain unclear.
To further elucidate the role of BACE1 during the development of Alzheimer Disease,we utilized yeast two-hybrid system to identify BACE1-interacting proteins. Using the BACE1 carboxyl terminus(C_(473-501)) as the bait protein,we screened the human fetal brain cDNA library and acquired one novel protein:pp6068 clone protein.
We constructed a pp6068 clone protein expression vector and expressed it in mammalian cells.Co-immunoprecipitantion in HEK 293T cells confirmed the interaction between pp6068 clone protein and BACE1.The overexpression of pp6068 clone protein in N2a/APP695 dramatically increases protein level of APP/βCTF and Aβ,both of which are hydrolysis products of BACE1.On the other hand,the increased expression of pp6068 clone protein decreaseα-secretase cleavage product of APP,sAPPα.
Our data suggests that pp6068 clone protein may play a potential role in the regulation of BACE1 activity and affect the APP processing and Aβgeneration.Our research may contribute to further comprehension of proteins interacting with BACE1, and facilitate developments in Alzheimer's disease treatment.
为了更清楚地认识和了解BACE1在阿尔茨海默症发病过程中的作用,我们实验室以BACE1的胞内端第473位至第501位氨基酸构建诱饵蛋白,利用酵母双杂交的方法在人胎脑cDNA文库进行筛选,得到一个能与BACE1相互作用的蛋白:pp6068克隆蛋白。
我们构建了pp6068克隆蛋白在哺乳动物细胞中的稳定表达的载体,免疫共沉淀实验证明外源性的pp6068克隆蛋白和BACE1在HEK293T细胞中能够发生相互作用。在N2a/APP695细胞中,pp6068克隆蛋白的过表达能够上调BACE1的水解产物APP/βCTF和Aβ的蛋白水平,同时,还能够下调α-分泌酶的水解产物sAPPα的蛋白水平。
这些研究说明,pp6068克隆蛋白可能参与了BACE1活性的调节,影响APP的降解和Aβ的形成。同时也可能对α-分泌酶对APP的水解过程产生了影响。对于与BACE1相互作用的蛋白的研究不仅有利于揭示pp6068克隆蛋白在哺乳动物中的生物学功能,还可能为研究BACE1生理功能和AD的治疗开辟新的途径。
Alzheimer's disease(AD) is a neurodegenerative disorder which is characterized clinically by progressive loss of memory and impairment of cognitive abilities. Neurofibrillary tangle(NFT) and senile plaque(SP) are the two histological characters found in the brain of AD patients.Recent researches have showed that the major component of SPs is Aβ(β-amyloid peptides).BACE1(β-site APP cleaving enzyme;APP,amyloid precursor protein),identified as a key enzyme during the Aβformation,has become one of the hotspots of Alzheimer's disease research.However, some pathophysiological functions of BACE1 and the underlying mechanisms still remain unclear.
To further elucidate the role of BACE1 during the development of Alzheimer Disease,we utilized yeast two-hybrid system to identify BACE1-interacting proteins. Using the BACE1 carboxyl terminus(C_(473-501)) as the bait protein,we screened the human fetal brain cDNA library and acquired one novel protein:pp6068 clone protein.
We constructed a pp6068 clone protein expression vector and expressed it in mammalian cells.Co-immunoprecipitantion in HEK 293T cells confirmed the interaction between pp6068 clone protein and BACE1.The overexpression of pp6068 clone protein in N2a/APP695 dramatically increases protein level of APP/βCTF and Aβ,both of which are hydrolysis products of BACE1.On the other hand,the increased expression of pp6068 clone protein decreaseα-secretase cleavage product of APP,sAPPα.
Our data suggests that pp6068 clone protein may play a potential role in the regulation of BACE1 activity and affect the APP processing and Aβgeneration.Our research may contribute to further comprehension of proteins interacting with BACE1, and facilitate developments in Alzheimer's disease treatment.
引文
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