2. Academic Validation
  3. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice

Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice

  • Neuropsychopharmacology. 2023 Nov 29. doi: 10.1038/s41386-023-01774-2.
Zhengjiang Qian 1,  Bowei Li 2,  Xin Meng 1,  Jianming Liao 3,  Guangxing Wang 4,  Yanjiao Li 1,  Qian Luo 5,  Keqiang Ye 6
Affiliations

Affiliations

  • 1 Faculty of Life and Health Sciences, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China.
  • 2 Shenzhen Institute of Advanced Technology, University of Chinese Academy of Science, Shenzhen, Guangdong, 518055, China.
  • 3 Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 4 School of Medicine, Tongji University, Shanghai, 200092, China.
  • 5 Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. qian.luo@siat.ac.cn.
  • 6 Faculty of Life and Health Sciences, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China. kq.ye@siat.ac.cn.
PMID: 38030711 DOI: 10.1038/s41386-023-01774-2
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aβ40 and Aβ42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aβ42 (mAβ42), mAβ40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPβ transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAβ aggregation as validated by Aβ PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.

Figures
Products