Metabolism of presenilin 1: Influence of presenilin 1 on amyloid precursor protein processing
Metabolism of presenilin 1: Influence of presenilin 1 on amyloid precursor protein processing
复制标题
DOI：
10.1016/s0197-4580(98)00026-8
复制
发表时间：
1998-01-01
影响因子：
4.2
通讯作者：
Borchelt, DR
中科院分区：
文献类型：
--
作者：
Borchelt, DR
为了建立模型系统来检测早老素1(PS1)在体内的代谢，我们产生了表达野生型和A246E突变的人PS1的转基因小鼠。我们的数据表明，野生型和突变型PS I都被内切为27 kDa的N末端片段和17 kDa的C末端片段，这是正常哺乳动物脑中发现的主要PS 1物种。为了检测突变PS 1对Aβ形成和在脑中沉积的影响，我们将表达野生型和突变PS 1的小鼠与表达带有人源化Aβ结构域的小鼠淀粉样前体蛋白(APP)和与瑞典家族性阿尔茨海默病家系(APP.swe)相关的错义突变的小鼠交配。在共表达突变型PS 1和APP.swe的小鼠的大脑中，Aβ1-42/43与1-40的比率比单独表达APP.swe的小鼠或表达APP.swe和野生型PS1的小鼠高50%。这些数据表明，PS1的突变可能通过增加更长、更具淀粉样变性的42和43残基Aβ多肽的浓度而导致早发性阿尔茨海默病。(C)1998年爱思唯尔科学公司。
To create model systems to examine presenilin 1 (PS1) metabolism in vivo, we generated transgenic mice expressing wild-type and A246E mutant human PS1. Our data indicate that both wild-type and mutant PS I is endoproteolytically cleaved into 27 kDa N- and 17 kDa C-terminal fragments, which are the principal PS 1 species found in normal mammalian brain. To examine the influence of mutant PS 1 on A beta formation and deposition in brain, we mated mice expressing wild-type and mutant PS 1 to mice expressing a murine amyloid precursor protein (APP) with a humanized A beta domain and missense mutations linked to a Swedish familial Alzheimer's disease kindred (APP.swe). In the brains of mice that co-express mutant PS 1 and APP.swe, the ratio of A beta 1-42/43 to 1-40 was elevated by 50% compared to mice expressing APP.swe alone or mice expressing APP.swe and wild-type PS1. These data suggest that mutations in PS1 may cause early onset Alzheimer's disease by enhancing the concentration of longer, and more amyloidogenic, 42 and 43 residue A beta peptides. (C) 1998 Elsevier Science Inc.