Qian S, Jiang P, Guan X M, Singh G, Trumbauer M E, Yu H, Chen H Y, Van de Ploeg L H, Zheng H
Department of Biochemistry and Physiology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Neuron. 1998 Mar;20(3):611-7. doi: 10.1016/s0896-6273(00)80999-x.
Mutations in presenilin 1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster production of Abeta1-42/43 in FAD patients and transgenic mice. PS1 null mice are embryonic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type human PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indicating that the mutation does not lead to loss of PS1 function during development. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mice does not lead to Abeta1-42/43 increase, whereas expression of human mutant PS1 on murine PS1 null background is sufficient to elevate Abeta1-42/43, supporting a gain-of-function activity as the result of the PS1 mutation.
早老素1（PS1）的突变与早发性家族性阿尔茨海默病（FAD）相关，并且在FAD患者和转基因小鼠中显示会促进β淀粉样蛋白1-42/43的产生。PS1基因敲除小鼠胚胎致死，并表现出轴向骨骼畸形和中枢神经系统缺陷。我们发现，表达野生型人PS1蛋白或携带A246E FAD突变的人PS1的转基因小鼠品系能够在相似程度上使PS1基因敲除小鼠从胚胎致死中获救，这表明该突变在发育过程中不会导致PS1功能丧失。此外，PS1（+/-）小鼠中PS1活性降低50%不会导致β淀粉样蛋白1-42/43增加，而在小鼠PS1基因敲除背景上表达人突变型PS1足以升高β淀粉样蛋白1-42/43，这支持了PS1突变导致功能获得性活性这一结果。
