Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice.
Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice.
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脑啡肽酶过度表达可抑制斑块形成，但不能减少人淀粉样前体蛋白转基因小鼠中的致病性 Abeta 寡聚体和相关认知缺陷。
DOI：
10.1523/jneurosci.2984-08.2009
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发表时间：
2009-02-18
期刊：
影响因子：
--
通讯作者：
Mucke L
中科院分区：
文献类型：
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作者：
Meilandt WJ;Cisse M;Ho K;Wu T;Esposito LA;Scearce-Levie K;Cheng IH;Yu GQ;Mucke L
阿尔茨海默病(AD)患者脑内淀粉样蛋白-β(A-β)多肽的蓄积可能是由于A-β的产生和清除失衡所致。在人类淀粉样前体蛋白(HAPP)转基因小鼠的大脑中过表达Aβ降解酶Neprilysin可以降低Aβ水平和淀粉样斑块负担。由于AD相关的突触和认知障碍似乎与Aβ寡聚体的关系比与斑块的关系更密切，因此确定Neprilysin活性的增加是否也会降低体内致病的Aβ寡聚体和相关的神经元缺陷的水平是很重要的。为了解决这个问题，我们将Happ转基因小鼠与neprilyin转基因小鼠杂交，并分析了它们的后代。Neprilysin过表达降低了50%的可溶性Aβ水平，并有效地阻止了新皮质和海马区早期Aβ的沉积。然而，它并没有降低Aβ三聚体和Aβ*56的水平，也没有改善空间学习和记忆方面的缺陷。Neprilysin对斑块和寡聚体的不同作用表明，依赖neprilysin的Aβ降解对斑块的影响大于对寡聚体的影响，这些结构可能是通过不同的组装机制形成的。奈普利辛无法预防HAPP小鼠的学习和记忆障碍，可能与其无法减少致病的Aβ寡聚体有关。抗Aβ治疗可能需要减少Aβ寡聚体以改善认知功能。
The accumulation of amyloid-β (Aβ) peptides in the brain of patients with Alzheimer’s disease (AD) may arise from an imbalance between Aβ production and clearance. Overexpression of the Aβ-degrading enzyme neprilysin in brains of human amyloid precursor protein (hAPP) transgenic mice decreases overall Aβ levels and amyloid plaque burdens. Because AD-related synaptic and cognitive deficits appear to be more closely related to Aβ oligomers than to plaques, it is important to determine if increased neprilysin activity also diminishes the levels of pathogenic Aβ oligomers and related neuronal deficits in vivo. To address this question, we crossed hAPP transgenic mice with neprilysin transgenic mice and analyzed their offspring. Neprilysin overexpression reduced soluble Aβ levels by 50% and effectively prevented early Aβ deposition in the neocortex and hippocampus. However, it did not reduce levels of Aβ trimers and Aβ*56 or improve deficits in spatial learning and memory. The differential effect of neprilysin on plaques and oligomers suggests that neprilysin-dependent degradation of Aβ affects plaques more than oligomers and that these structures may form through distinct assembly mechanisms. Neprilysin’s inability to prevent learning and memory deficits in hAPP mice may be related to its inability to reduce pathogenic Aβ oligomers. Reduction of Aβ oligomers will likely be required for anti-Aβ treatments to improve cognitive functions.