Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
J Neurosci Res. 2011 Jun;89(6):808-14. doi: 10.1002/jnr.22603. Epub 2011 Mar 3.
Three loci that modify β-amyloid (Aβ) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aβ by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aβ deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Aβ in both the blood and the brain, confirming brain Aβ's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aβ accumulation.
先前已有研究描述了三个可改变阿尔茨海默病小鼠模型中β-淀粉样蛋白（Aβ）积累和沉积的基因座。其中一个包含编码早老素 2 的 Psen2 基因，早老素 2 是 γ-分泌酶活性的组成部分，负责通过蛋白水解生成 Aβ。我们发现，小鼠 Psen2 的活性（通过 mRNA 积累水平来衡量）出人意料地在肝脏中具有遗传性，但在大脑中没有遗传性，这表明肝脏是大脑 Aβ 沉积的起源。施用 STI571（一种不能穿透血脑屏障的癌症治疗药物）可减少 Aβ 在血液和大脑中的积累，这证实了大脑 Aβ 的外周起源，并表明 STI571 和相关化合物可能对人类阿尔茨海默病具有治疗/预防价值。Cib1 和 Zfhx1b 基因位于其他修饰基因座内，在肝脏中也具有遗传性表达，这表明它们也有助于 Aβ 的积累。
