Amyloid β (Aβ) accumulation in the brain is considered to be one of the major pathological changes in the progression of Alzheimer's disease (AD). Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades Aβ. However, conventional approaches for increasing NEP levels or inducing its activation via viral-vector gene delivery have been shown to be problematic due to complications involving secondary toxicity, immune responses, and/or low gene transfer efficiency. Thus, in the present study, a physical and tractable NEP gene-delivery system via ultrasound (US) combined with microbubbles was developed for AD therapy. We introduced the plasmid, human NEP (hNEP), into skeletal muscle of 6-month-old amyloid precursor protein/presenilin-1 (APP/PS1) AD mice. Interestingly, we found a significantly reduced Aβ burden in the brain at 1 month after the delivery of overexpressed hNEP into skeletal muscle. Moreover, hNEP-treated AD mice exhibited improved performance in the Morris water maze compared to that of untreated AD mice. In addition, there were no apparent injuries in the injected muscle or in the lungs or kidneys at 1 month after the delivery of hNEP into skeletal muscle. These findings suggest that the introduction of hNEP into skeletal muscle via US represents an effective and safe therapeutic strategy for ameliorating AD-like symptoms in APP/PS1 mice, which may have the potential for clinical applications in the future.

中文翻译：

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Neprilysin在骨骼肌中的表达通过超声介导的基因转移（声处理）减少了AD的淀粉样蛋白负担。

淀粉样蛋白β（Aβ）在大脑中的积累被认为是阿尔茨海默病（AD）进展的主要病理变化之一。脑啡肽酶（NEP）是一种锌金属肽酶，可有效降解Aβ。然而，由于涉及继发毒性，免疫应答和/或低基因转移效率的并发症，用于增加NEP水平或通过病毒载体基因递送诱导其活化的常规方法已显示出问题。因此，在本研究中，开发了通过超声（US）结合微泡的物理且易于处理的NEP基因递送系统，用于AD治疗。我们将质粒人NEP（hNEP）引入了6个月大的淀粉样蛋白前体蛋白/早老素-1（APP / PS1）AD小鼠的骨骼肌。有趣的是 我们发现在将过表达的hNEP传递至骨骼肌后1个月，大脑中的Aβ负担显着降低。而且，与未处理的AD小鼠相比，hNEP处理的AD小鼠在莫里斯水迷宫中表现出改善的性能。此外，在将hNEP输送至骨骼肌后1个月，注射的肌肉，肺或肾脏均无明显损伤。这些发现表明，通过US将hNEP引入骨骼肌代表了一种改善APP / PS1小鼠AD样症状的有效且安全的治疗策略，这在将来可能具有临床应用潜力。此外，在将hNEP输送至骨骼肌后1个月，注射的肌肉，肺或肾脏均无明显损伤。这些发现表明，通过US将hNEP引入骨骼肌代表了一种改善APP / PS1小鼠AD样症状的有效且安全的治疗策略，这在将来可能具有临床应用潜力。此外，在将hNEP输送至骨骼肌后1个月，注射的肌肉，肺或肾脏均无明显损伤。这些发现表明，通过US将hNEP引入骨骼肌代表了一种改善APP / PS1小鼠AD样症状的有效且安全的治疗策略，这在将来可能具有临床应用潜力。