Peripheral Reduction of β-Amyloid Is Sufficient To Reduce Brain β-Amyloid: Implications for Alzheimer's Disease
Peripheral Reduction of β-Amyloid Is Sufficient To Reduce Brain β-Amyloid: Implications for Alzheimer's Disease
复制标题
DOI：
10.1002/jnr.22603
复制
发表时间：
2011-06-01
影响因子：
4.2
通讯作者：
Hilbush, Brian S.
中科院分区：
文献类型：
--
作者：
Sutcliffe, J. Gregor;Hedlund, Peter B.;Hilbush, Brian S.
先前已经描述了三个改变阿尔茨海默病小鼠模型大脑中β-淀粉样蛋白(Aβ)积累和沉积的基因座。一种包括编码早老素2的PSEN2基因，这是伽马分泌酶活性的一种成分，负责通过蛋白质分解产生Aβ。我们发现，通过mRNA积累水平衡量，小鼠PSEN2的活性出人意料地在肝脏中可遗传，但在脑中不可遗传，这表明肝脏是脑Aβ沉积的来源。STI571是一种不会跨越血脑屏障的癌症治疗药物，它的应用减少了Aβ在血液和大脑中的积聚，证实了脑Aβ的外周来源，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，在肝脏中也表现出可遗传的表达，这表明它们也有助于Aβ的积累。(C)2011年Wiley-Liss，Inc.
Three loci that modify beta-amyloid (A beta) 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 gamma-secretase activity responsible for generating A beta 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 A beta deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of A beta in both the blood and the brain, confirming brain A beta'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 A beta accumulation. (C) 2011 Wiley-Liss, Inc.