Neprilysin protects neurons against Aβ peptide toxicity
Neprilysin protects neurons against Aβ peptide toxicity
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DOI：
10.1016/j.brainres.2007.03.072
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发表时间：
2007-06-04
期刊：
影响因子：
2.9
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.
近年来，研究表明，大脑中β淀粉样蛋白（Aβ）肽的积累在阿尔茨海默病（AD）的发展中发挥着关键作用。大脑中 Aβ 肽的稳态水平取决于淀粉样前体蛋白 (APP) 通过 β 和 γ 分泌酶的生成速率以及多种酶活性的降解速率。脑啡肽酶 (NEP) 似乎是大脑中最有效的 Aβ 肽降解酶。 NEP 活性的降低（由于基因突变、年龄或改变 NEP 表达或活性的疾病）可能会导致神经毒性 Aβ 肽在大脑中积聚；反过来，这会导致神经元损失。我们研究了慢病毒介导的 NEP 过表达在体外保护神经元细胞免受 Aβ 肽侵害的功效。将过表达 NEP 的海马神经元细胞 (HT22) 与 A β 肽单体一起孵育，可降低 A β 肽对神经元细胞的毒性（通过细胞活力测量）。我们得出的结论是，通过基因治疗方法在 AD 大脑中易受 Aβ 肽聚集的区域过度表达 NEP 可能会保护神经元免受 Aβ 肽的毒性作用，这有望成为改变 AD 发展的巨大潜在靶点。 (c) 2007 Elsevier B.V. 保留所有权利。
In recent years, studies have suggested that accumulation of amyloid beta (A beta) peptide in the brain plays a key role in the development of Alzheimer's disease (AD). The steady-state level of A beta peptide in the brain is determined by the rate of production from amyloid precursor protein (APP) via beta- and gamma-secretases and degradation by the activity of several enzymes. Neprilysin (NEP) appears to be the most potent A beta peptide-degrading enzyme in the brain. Decreasing the activity of NEP (due to genetic mutations, age or diseases that alter the expression or activity of NEP) may lead to accumulation of the neurotoxic A beta peptide in the brain; in turn this leads to neuronal loss. We investigated the efficacy of lentivirus-mediated over-expression of NEP to protect neuronal cells from A beta peptide in vitro. Incubation of hippocampal neuronal cells (HT22) over-expressing NEP with the monomeric from of A beta peptide decreases the toxicity of A beta peptide on the neuronal cells, as measured through cell viability. We conclude that over-expression of NEP by a gene therapy approach in areas vulnerable to A beta peptide aggregation in AD brain may protect the neurons from the toxicity effects of A beta peptide and this promises a great potential target for altering the development of AD. (c) 2007 Elsevier B.V. All rights reserved.