Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease

[摘要] 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 (delta-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes A beta production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized delta-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks delta-secretase activity separately, and their combination synergistically blunts delta-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal delta-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by delta-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress delta-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate delta-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.

[发布日期] 2021-10-01

[关键词] CF3CN;#11a;BDNF;Delta-secretase;Neuroprotection;Alzheimer's disease