El-Amouri Salim S, Zhu Hong, Yu Jin, Marr Robert, Verma Inder M, Kindy Mark S
Department of Molecular and Cellular Biochemistry, Medical University of South Carolina, Charleston, SC 29425, USA.
Am J Pathol. 2008 May;172(5):1342-54. doi: 10.2353/ajpath.2008.070620. Epub 2008 Apr 10.
It is well established that the extracellular deposition of amyloid beta (Abeta) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of Abeta peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant Abeta peptide-degrading enzyme in the brain; NEP becomes inactivated and down-regulated during both the early stages of AD and aging. In this study, we investigated the effect of human (h)NEP gene transfer to the brain in a mouse model of AD before the development of amyloid plaques, and assessed how this treatment modality affected the accumulation of Abeta peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/DeltaPS1 double-transgenic mice resulted in reduction in Abeta peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. Moreover, the overall reduction in amyloidosis and associated pathogenetic changes in the brain resulted in decreased memory impairment by approximately 50%. These data suggest that restoring NEP levels in the brain at the early stages of AD is an effective strategy to prevent or attenuate disease progression.
淀粉样β（Aβ）肽的细胞外沉积在阿尔茨海默病（AD）的发展中起着核心作用，这一点已得到充分证实。因此，阻止Aβ肽在大脑中积累或加速其清除可能会减缓AD发病的速度。中性内肽酶（NEP）是大脑中主要的Aβ肽降解酶；在AD早期和衰老过程中，NEP都会失活并下调。在本研究中，我们在淀粉样斑块形成之前的AD小鼠模型中研究了人（h）NEP基因转移至大脑的效果，并评估了这种治疗方式如何影响Aβ肽的积累以及相关的致病变化（如炎症、氧化应激和记忆障碍）。在年轻的APP/DeltaPS1双转基因小鼠中过表达hNEP 4个月，可导致Aβ肽水平降低、淀粉样蛋白负荷减轻、氧化应激和炎症减轻，并改善空间定向能力。此外，大脑中淀粉样变性及相关致病变化的总体减轻使记忆障碍减少了约50%。这些数据表明，在AD早期恢复大脑中的NEP水平是预防或减轻疾病进展的有效策略。
