Department of Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, Lexington, KY 40536-0509, USA.
Mol Cell Neurosci. 2010 Oct;45(2):101-7. doi: 10.1016/j.mcn.2010.05.014. Epub 2010 Jun 15.
The use of the peptidase neprilysin (NEP) as a therapeutic for lowering brain amyloid burden is receiving increasing attention. We have previously demonstrated that peripheral expression of NEP on the surface of hindlimb muscle lowers brain amyloid burden in a transgenic mouse model of Alzheimer's disease. In this study we now show that using adeno-associated virus expressing a soluble secreted form of NEP (secNEP-AAV8), NEP secreted into plasma is effective in clearing brain Abeta. Soluble NEP expression in plasma was sustained over the 3-month time period it was measured. Secreted NEP decreased plasma Abeta by 30%, soluble brain Abeta by approximately 28%, insoluble brain Abeta by approximately 55%, and Abeta oligomersby 12%. This secNEP did not change plasma levels of substance P or bradykinin, nor did it alter blood pressure. No NEP was detected in CSF, nor did the AAV virus produce brain expression of NEP. Thus the lowering of brain Abeta was due to plasma NEP which altered blood-brain Abeta transport dynamics. Expressing NEP in plasma provides a convenient way to monitor enzyme activity during the course of its therapeutic testing.
神经肽酶 Neprilysin（NEP）作为降低脑淀粉样蛋白负荷的治疗方法正受到越来越多的关注。我们之前已经证明，在阿尔茨海默病的转基因小鼠模型中，外周表达 NEP 可降低脑淀粉样蛋白负荷。在这项研究中，我们现在表明，使用表达可溶性分泌型 NEP（secNEP-AAV8）的腺相关病毒，分泌到血浆中的 NEP 可有效清除脑内 Abeta。可溶的 NEP 在血浆中的表达在 3 个月的测量期间得以维持。分泌的 NEP 使血浆中的 Abeta 降低了 30%，可溶性脑 Abeta 降低了约 28%，不溶性脑 Abeta 降低了约 55%，Abeta 寡聚物降低了 12%。这种 secNEP 没有改变血浆中 P 物质或缓激肽的水平，也没有改变血压。CSF 中未检测到 NEP，AAV 病毒也没有在大脑中表达 NEP。因此，脑内 Abeta 的降低是由于血浆中的 NEP 改变了血脑 Abeta 转运动力学。在血浆中表达 NEP 为监测其治疗试验过程中的酶活性提供了一种便利的方法。
