Neprilysin: An enzyme candidate to slow the progression of Alzheimer's disease
Neprilysin: An enzyme candidate to slow the progression of Alzheimer's disease
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DOI：
10.2353/ajpath.2008.070620
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发表时间：
2008-05-01
影响因子：
6
通讯作者：
Kindy, Mark S.
中科院分区：
文献类型：
--
作者：
El-Amouri, Salim S.;Zhu, Hong;Kindy, Mark S.
已经充分确定淀粉样β（A β）肽的细胞外沉积在阿尔茨海默病（AD）的发展中起中心作用。因此，防止A β肽在大脑中的积累或加速其清除可能会减缓AD发作的速率。脑啡肽酶（NEP）是脑中主要的A β肽降解酶; NEP在AD和衰老的早期阶段变得失活和下调。在这项研究中，我们研究了在淀粉样斑块形成之前，人（h）NEP基因转移到AD小鼠模型的脑中的效果，并评估了这种治疗方式如何影响A β肽的积累和相关的病理变化（例如，炎症、氧化应激和记忆障碍）。在年轻的APP/Delta PS1双转基因小鼠中过表达hNEP 4个月导致A β肽水平降低，淀粉样蛋白负荷减弱，氧化应激和炎症，以及空间定向改善。此外，淀粉样变性和脑中相关病理变化的总体减少导致记忆障碍减少了约50%。这些数据表明，在AD的早期阶段恢复脑中的NEP水平是预防或减缓疾病进展的有效策略。
it is well established that the extracellular deposition of amyloid beta (A beta) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of A beta peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant A beta 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 A beta peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/Delta PS1 double-transgenic mice resulted in reduction in A beta 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 similar to 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.