Spencer Brian, Marr Robert A, Rockenstein Edward, Crews Leslie, Adame Anthony, Potkar Rewati, Patrick Christina, Gage Fred H, Verma Inder M, Masliah Eliezer
Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA.
BMC Neurosci. 2008 Nov 12;9:109. doi: 10.1186/1471-2202-9-109.
Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-beta (Abeta) peptide in the brain. The endopeptidase, neprilysin, has been implicated as a major Abeta degrading enzyme in mice and humans. Previous short and intermediate term studies have shown the potential therapeutic application of neprilysin by delivering this enzyme into the brain of APP transgenic mice using gene transfer with viral vectors. However the effects of long-term neprilysin gene transfer on other aspects of Abeta associated pathology have not been explored yet in APP transgenic mice.
We show that the sustained expression of neprilysin for up to 6 months lowered not only the amyloid plaque load but also reduced the levels of intracellular Abeta immunoreactivity. This was associated with improved behavioral performance in the water maze and ameliorated the dendritic and synaptic pathology in the APP transgenic mice.
These data support the possibility that long-term neprilysin gene therapy improves behavioral and neurodegenerative pathology by reducing intracellular Abeta.
蛋白水解降解已成为控制大脑中与阿尔茨海默病（AD）相关的淀粉样β（Aβ）肽水平的关键途径。内肽酶中性内肽酶已被认为是小鼠和人类中主要的Aβ降解酶。先前的短期和中期研究表明，通过使用病毒载体进行基因转移将这种酶递送至APP转基因小鼠的大脑中，中性内肽酶具有潜在的治疗应用。然而，长期中性内肽酶基因转移对APP转基因小鼠中Aβ相关病理学其他方面的影响尚未得到探索。
我们表明，长达6个月的中性内肽酶持续表达不仅降低了淀粉样斑块负荷，还降低了细胞内Aβ免疫反应性水平。这与水迷宫中行为表现的改善相关，并改善了APP转基因小鼠的树突和突触病理学。
这些数据支持长期中性内肽酶基因治疗通过降低细胞内Aβ来改善行为和神经退行性病理学的可能性。
