Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aβ production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.

阿尔茨海默病 (AD) 是最常见的痴呆症，目前尚无改善疾病的治疗药物。BDNF/TrkB 信号在 AD 中受损并且与显着的 delta 分泌酶（δ 分泌酶，也称为天冬酰胺内肽酶或 legumain）激活相关，它同时切割 APP 和 Tau 并促进 Aβ 产生和神经原纤维缠结 (NFT) 病理。在这里，我们展示了优化的 δ-分泌酶抑制剂 (#11a) 或 TrkB 受体激动剂 (CF3CN) 分别有效地阻断了 δ-分泌酶活性，并且它们的组合协同地减弱了 δ-分泌酶，在 3xTg AD 小鼠模型中表现出有前途的治疗效果。最佳的 δ-分泌酶抑制剂显示出可证明的脑暴露和口服生物利用度，抑制 δ-分泌酶对 APP N585 和 Tau N368 的切割。引人注目的是，CF3CN 处理明显提高了 BDNF 水平。#11a 和 CF3CN 都表现出很强的体内PK/PD 特性和抑制大脑中 δ-分泌酶活性的能力。口服 CF3CN 强烈激活 TrkB，触发活性 Akt 磷酸化 δ-分泌酶 T322，防止其蛋白水解激活并减轻 AD 病理。#11a 或 CF3CN 显着减少 AD 发病机制并改善认知功能，组合表现出最大效果。因此，我们的数据支持这些衍生物是治疗 AD 的强大候选药物。