Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.
Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.
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DOI：
10.1093/brain/awt308
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Webster CI
中科院分区：
文献类型：
--
作者：
Henderson SJ;Andersson C;Narwal R;Janson J;Goldschmidt TJ;Appelkvist P;Bogstedt A;Steffen AC;Haupts U;Tebbe J;Freskgård PO;Jermutus L;Burrell M;Fowler SB;Webster CI
降低外周淀粉样蛋白-β的水平已被提出作为减少阿尔茨海默病患者斑块的策略。亨德森等人在大鼠、猴子和Tg2576小鼠中测试淀粉样蛋白降解酶脑啡肽酶的改良版本。血液中的淀粉样蛋白-β水平降低，但CNS中的淀粉样蛋白水平没有降低。阿尔茨海默病的特征是大脑中淀粉样蛋白沉积的积累和认知功能的进行性丧失。虽然淀粉样蛋白-β在疾病进展中的确切作用仍然存在一定争议，但许多阻止或逆转疾病进展的努力都集中在减少其合成或增强其去除上。据信，脑和外周可溶性淀粉样蛋白-β处于平衡状态，并且先前已经假设外周淀粉样蛋白-β的减少可以降低脑淀粉样蛋白-β，从而减少主要由不溶性淀粉样蛋白-β组成的斑块的形成;所谓的外周汇假说。在此，我们描述了淀粉样蛋白-β降解酶（内源性金属肽酶脑啡肽酶）的使用，该酶与白蛋白融合以延长血浆半衰期，并经工程改造以增强淀粉样蛋白-β降解活性。我们使用该分子研究了Tg2576转基因小鼠重复静脉给药长达4个月以及大鼠和猴重复静脉给药1个月后，外周淀粉样蛋白-β降解对脑和脑脊液中淀粉样蛋白-β水平的影响。这种分子被证明在外周中降解淀粉样蛋白-β非常有效，但不改变脑或脑脊液淀粉样蛋白-β水平，表明外周汇假说是无效的，这是第一次在非人类灵长类动物中得到证实。
Lowering levels of peripheral amyloid-β has been proposed as a strategy to reduce plaques in patients with Alzheimer’s disease. Henderson et al. test a modified version of the amyloid-degrading enzyme neprilysin in rats, monkeys and Tg2576 mice. Levels of amyloid-β were reduced in the bloodstream, but not in the CNS. Alzheimer’s disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-β in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-β are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby reducing formation of plaques predominantly composed of insoluble amyloid-β; the so-called peripheral sink hypothesis. Here we describe the use of an amyloid-β degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to albumin to extend plasma half-life and has been engineered to confer increased amyloid-β degradation activity. We used this molecule to investigate the effect of degradation of peripheral amyloid-β on amyloid-β levels in the brain and cerebrospinal fluid after repeated intravenous dosing for up to 4 months in Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved highly effective at degradation of amyloid-β in the periphery but did not alter brain or cerebrospinal fluid amyloid-β levels, suggesting that the peripheral sink hypothesis is not valid and is the first time that this has been demonstrated in non-human primates.
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DOI：
10.1523/jneurosci.4560-08.2009
发表时间：
2009-04-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Karlnoski RA;Rosenthal A;Kobayashi D;Pons J;Alamed J;Mercer M;Li Q;Gordon MN;Gottschall PE;Morgan D
通讯作者：
Morgan D
影响因子：
4.8
作者：
Leissring, MA;Lu, A;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
5.3
作者：
Comery, TA;Martone, RL;Marquis, KL
通讯作者：
Marquis, KL
影响因子：
6
作者：
El-Amouri, Salim S.;Zhu, Hong;Kindy, Mark S.
通讯作者：
Kindy, Mark S.
影响因子：
82.9
作者：
Deane, R;Yan, SD;Zlokovic, B
通讯作者：
Zlokovic, B