Efflux of human and mouse amyloid β proteins 1-40 and 1-42 from brain:: Impairment in a mouse model of Alzheimer's disease
Efflux of human and mouse amyloid β proteins 1-40 and 1-42 from brain:: Impairment in a mouse model of Alzheimer's disease
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DOI：
10.1016/s0306-4522(03)00474-3
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Morley, JE
中科院分区：
文献类型：
--
作者：
Banks, WA;Robinson, SM;Morley, JE
大脑到血液的运输被认为是大脑中发现的淀粉样β蛋白(AbetaP)数量的主要决定因素。外流受损被认为是AbetaP在中枢神经系统蓄积从而导致阿尔茨海默病(AD)的一种机制。然而，到目前为止，还没有对与AD最相关的AbetaP形式AbetaP1-42的外流进行研究，尽管AbetaP中的单个氨基酸替代可以极大地改变AbetaP的外流。在这里，我们研究了AbetaP小鼠1-42、小鼠1-40、人1-42和人1-40在年轻CD-1、年轻衰老加速小鼠(SAM)P8和老年SAMP8小鼠中的外流。随着年龄的增长，SAMP8小鼠自发地过度产生AbetaP，并发展出被AbetaP导向的抗体或硫代反义寡核苷酸逆转的认知障碍。CD-1小鼠转运所有形式的AbetaP，尽管小鼠1-42和人1-40的转运速度比其他形式更快。SAMP8小鼠无论年龄大小，其可饱和转运的MUSE1-42均减少。小鼠1-40和人1-42在幼年SAMP8小鼠中仅以非饱和机制外流，而在老年SAMP8小鼠中完全不外流。这些不同形式的AbetaP外流在三组小鼠之间的差异支持了这样的假说，即外流受损是AbetaP在中枢神经系统积聚的重要因素。爱思唯尔有限公司代表IBRO出版。
Brain to blood transport is believed to be a major determinant of the amount of amyloid beta protein (AbetaP) found in brain. Impaired efflux has been suggested as a mechanism by which AbetaP can accumulate in the CNS and so lead to Alzheimer's disease (AD). To date, however, no study of the efflux of the form of AbetaP most relevant to AD, AbetaP1-42, has been conducted, even though a single amino acid substitution in AbetaP can greatly alter efflux. Here, we examined the efflux of AbetaP mouse1-42, mouse1-40, human1-42, and human1-40 in young CD-1, young senesence accelerated mouse (SAM) P8, and aged SAMP8 mice. The SAMP8 mouse with aging spontaneously overproduces AbetaP and develops cognitive impairments reversed by AbetaP-directed antibody or phosphorothioate antisense oligonucleotide. CD-1 mice transported all forms of AbetaP, although mouse1-42 and human1-40 were transported faster than the other forms. There was a decrease in the saturable transport of mouse1-42 in SAMP8 mice regardless of age. Efflux of mouse1-40 and human1-42 was only by a non-saturable mechanism in young SAMP8 mice and their efflux was totally absent in aged SAMP8 mice. These differences in the efflux of the various forms of AbetaP among the three groups of mice supports the hypothesis that impaired efflux is an important factor in the accumulation of AbetaP in the CNS. Published by Elsevier Ltd on behalf of IBRO.