Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer's disease-related pathologies in a senescence-accelerated mouse model.
Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer's disease-related pathologies in a senescence-accelerated mouse model.
复制标题
δ-分泌酶抑制剂 11 对天冬酰胺酰内肽酶的药理学抑制可减轻衰老加速小鼠模型中与阿尔茨海默氏病相关的病理学
DOI：
10.1186/s40035-021-00235-4
复制
发表时间：
2021-03-31
影响因子：
12.6
通讯作者：
Song M
中科院分区：
文献类型：
--
作者：
Wang J;Hu HJ;Liu ZK;Liu JJ;Wang SS;Cheng Q;Chen HZ;Song M
目前，还没有治愈阿尔茨海默病（AD）的方法。迫切需要能够改变AD早期阶段的治疗药物。最近的研究表明，AD的发病机制是密切调节的内/溶酶体天冬酰胺酰内肽酶（AEP）。已报道抑制AEP可预防AD转基因小鼠模型中的神经变性。然而，超过90%的AD病例是与年龄相关的散发性AD，而不是遗传性AD。AEP抑制剂在年龄相关散发性AD中的治疗效果尚不清楚。选择衰老加速小鼠易感8（SAMP 8）作为散发性AD的近似模型，并用选择性AEP抑制剂：δ-分泌酶抑制剂11处理。通过酶活性测定来确定AEP的激活。ELISA法测定脑内可溶性β淀粉样蛋白（Aβ）含量。采用Morris水迷宫实验评价大鼠学习记忆相关认知能力。通过形态学和蛋白质印迹分析探讨脑中的病理变化。SAMP 8小鼠脑AEP酶活性显著高于SAMR 1小鼠。δ-分泌酶抑制剂11在体外抑制AEP的半数最大抑制浓度（IC 50）约为150 nM。δ-分泌酶抑制剂11长期治疗可显著降低脑AEP活性，减少Aβ1-40/42的产生，改善记忆力减退。用该试剂抑制AEP不仅减少了AEP切割的tau片段和tau过度磷酸化，而且还减弱了小胶质细胞活化形式的神经炎症。此外，用δ-分泌酶抑制剂11处理防止SAMP 8小鼠脑中的突触损失并减轻树突破坏。在散发性AD模型中，药物抑制AEP可以干预和预防AD样病理进展。脑内AEP的上调可能是AD早期治疗的一个有希望的靶点。δ-分泌酶抑制剂11可用作AD治疗的翻译开发的先导化合物。在线版本包含补充材料，可通过10.1186/s40035-021-00235-4获得。
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. 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. 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 (IC50) 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 Aβ1–40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain. Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment. The online version contains supplementary material available at 10.1186/s40035-021-00235-4.
登录
查看更多内容
影响因子：
5.8
作者：
Zhang Z;Xie M;Ye K
通讯作者：
Ye K
影响因子：
4.2
作者：
van Olst, Lynn;Verhaege, Daan;de Vries, Helga E.
通讯作者：
de Vries, Helga E.
影响因子：
12.6
作者：
Gauthier S;Zhang H;Ng KP;Pascoal TA;Rosa-Neto P
通讯作者：
Rosa-Neto P
影响因子：
9.3
作者：
Minett T;Classey J;Matthews FE;Fahrenhold M;Taga M;Brayne C;Ince PG;Nicoll JA;Boche D;MRC CFAS
通讯作者：
MRC CFAS
天冬酰胺内肽酶切割 tau 介导阿尔茨海默氏病的神经原纤维病理
影响因子：
82.9
作者：
通讯作者：
--