Humpel Christian
Laboratory of Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Austria.
Front Aging Neurosci. 2021 Apr 22;13:649646. doi: 10.3389/fnagi.2021.649646. eCollection 2021.
Alzheimer's disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small Aβ depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the Aβ degrading enzyme neprilysin delivered to the mouse brain can clear Aβ plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect.
阿尔茨海默病（AD）的病理特征是大脑中存在细胞外β-淀粉样蛋白（Aβ）斑块和神经元内tau缠结。一种治疗策略旨在预防或清除这些Aβ斑块，而Aβ降解酶中性内肽酶是一种降解斑块的有效药物。主要挑战在于通过血脑屏障将具有生物活性的中性内肽酶输送到大脑中。本研究的目的是探讨经鼻递送中性内肽酶是否能消除转基因AD小鼠模型（APP_SweDI）中的斑块。我们将测试胶原蛋白或血小板是否是将中性内肽酶输送到大脑的有效载体。使用成年转基因APP_SweDI小鼠的脑片培养物，我们发现单独的中性内肽酶或负载在胶原蛋白水凝胶或血小板中的中性内肽酶可清除皮质斑块。单独经鼻递送中性内肽酶可增加转基因小鼠中脑和尾皮质中的小Aβ沉积物。经鼻应用后，负载中性内肽酶的血小板可清除额叶皮质中的斑块。经鼻递送负载胶原蛋白的中性内肽酶对清除斑块非常有效，尤其是在皮质的中尾部。我们的数据支持将Aβ降解酶中性内肽酶递送至小鼠大脑可清除Aβ斑块，且经鼻递送（尤其是以胶原蛋白作为载体）是一种快速简便的给药方式。然而，必须考虑到经鼻给予中性内肽酶作为副作用可能也会在转基因小鼠大脑中激活更多斑块生成。
