Destablization of LRP family receptors by Alzheimer-related presenilin mutations

LDL受体相关蛋白（LRP）家族是阿尔茨海默病（AD）研究的热点 因为它包括几种载脂蛋白E（ApoE）的受体，以及 后者的基因（APOE）创造了人口统计学上最重要的遗传风险因素， 发展AD。另一个遗传贡献是由早老素（PS）-1和- 2;这些基因中的突变是早发性AD遗传的最大部分原因， 常染色体显性的方式。初步数据表明，这种PS1突变体减少了 LRP的稳态水平低于野生型PS1所见。拟议的研究将 进一步描述这种关系，并测试所涉及的机制和后果 LRP功能。这些研究的成功完成将为一个新的假设提供信息， 将LRP功能障碍置于AD发病机制的共同机制的中心点。

The LDL receptor-related protein (LRP) family is of interest in Alzheimer disease (AD) research because it includes several receptors for apolipoprotein E (ApoE), and polymorphisms in the gene for the latter (APOE) create the most demographically significant genetic risk factor for developing AD. Another genetic contribution is made by the genes for presenilins (PS)-1 and - 2; mutations in these genes are responsible for the largest fraction of early-onset AD inherited in an autosomal-dominant manner. Preliminary data indicate that such PS1 mutants reduce the steady-state levels of LRPs below what is seen with wild-type PS1. The proposed studies will characterize this relationship further and test the mechanisms involved and the consequences for LRP function. Successful completion of these studies will inform a novel hypothesis that places LRP dysfunction at a central point in the mechanisms common to AD pathogenesis.