Metzendorf Nicole G, Godec Ana, Petrovic Alex, Chourlia Aikaterini, Napoleone Antonino, Syvänen Stina, Rofo Fadi, Hultqvist Greta
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden.
Department of Pharmacy, Uppsala University, Husargatan 3, Box 580, Uppsala 751 23, Sweden.
Biomed Pharmacother. 2025 Aug;189:118325. doi: 10.1016/j.biopha.2025.118325. Epub 2025 Jul 8.
Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST).
We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mutation in Aβ (APP).
Our findings demonstrate a significant increase in neprilysin levels, which correlates with a reduction in various forms of Aβ, including membrane-bound and intracellular Aβ aggregates, as well as Aβ42 in insoluble aggregates.
These results suggest that neprilysin can effectively degrade Aβ with the Arctic mutation. Additionally, this treatment strategy successfully reduces both oligomeric and larger Aβ, aggregates, a challenge for other therapeutic approaches. This novel strategy holds promise as a potential therapeutic approach for AD.
中性内肽酶是负责降解β淀粉样蛋白（Aβ）的主要酶，其水平受生长抑素（SST）调节。
我们通过将SST与血脑屏障（BBB）转运体和Fc片段结合以延长其半衰期，开发了一种治疗阿尔茨海默病（AD）的新机制。该治疗方法在过表达带有Aβ北极突变的淀粉样前体蛋白（APP）的小鼠AD模型中进行了测试。
我们的研究结果表明中性内肽酶水平显著升高，这与各种形式的Aβ减少相关，包括膜结合和细胞内Aβ聚集体以及不溶性聚集体中的Aβ42。
这些结果表明中性内肽酶可以有效降解带有北极突变的Aβ。此外，这种治疗策略成功减少了寡聚体和更大的Aβ聚集体，这是其他治疗方法面临的挑战。这种新策略有望成为AD的一种潜在治疗方法。
