Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer’s disease-related pathologies in a senescence-accelerated mouse model

作者：Ju Wang, Hui‐Jie Hu, Zikai Liu, Jingjing Liu, Shanshan Wang, Qing Cheng, Hongzhuan Chen, Mingke Song · 发表于：Translational Neurodegeneration · 年份：2021 · DOI：10.1186/s40035-021-00235-4 · 被引用次数：23 · 研究领域：Protease and Inhibitor Mechanisms、Peptidase Inhibition and Analysis、Biochemical and Structural Characterization

Abstract Background Currently, there is no cure for Alzheimer’s disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown. Methods The senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses. Results The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC 50 ) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ 1–40/42 and ameliorated memory loss. The inhibition of...