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

Neuropsychopharmacology volume 49, pages 620–630 (2024)Cite this article

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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.

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Fig. 1: In vivo pharmacokinetics (PK) profiles of #11 A by the treatment of intravenous (I.V.) injection and oral administration (P.O.) in CD1 mouse.
Fig. 2: Acute treatment with #11 A inhibits activity of AEP and its downstream targets in Tau P301S mouse.
Fig. 3: Acute treatment with #11 A inhibits activity of AEP and its downstream targets in Thy1-ApoE4/C/EBPβ Tg mouse.
Fig. 4: Repeated treatment with #11 A inhibits Aβ deposition and Tau pathology in Thy1-ApoE4/C/EBPβ Tg mouse.
Fig. 5: Repeated treatment with #11 A inhibits neuronal loss and improve cognitive function in Thy1-ApoE4/C/EBPβ Tg mouse.

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Funding

This work was supported by Start-up fund from SIAT and the National Natural Science Foundation of China (32330040) to KY, the Guangdong Basic and Applied Basic Research Foundation (2023A1515030296) and the Shenzhen Government Basic Research Program (JCYJ20220531100802005) to ZQ, and the National Natural Science Foundation of China (32200928) to YL, and the “Hundred, Thousand and Ten Thousand” Science and Technology Major Special Project of Heilongjiang Province (No. 2020ZX07B01) to QL.

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Authors and 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

    Zhengjiang Qian, Xin Meng, Yanjiao Li & Keqiang Ye

  2. Shenzhen Institute of Advanced Technology, University of Chinese Academy of Science, Shenzhen, Guangdong, 518055, China

    Bowei Li

  3. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

    Jianming Liao

  4. School of Medicine, Tongji University, Shanghai, 200092, China

    Guangxing Wang

  5. Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Qian Luo

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Contributions

KY conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. ZQ designed and performed most of the experiments, analyzed the data and wrote the manuscript. BL performed the SiMoA experiments. XM and GW performed the LC-MS/MS analysis. JL performed part of the immunofluorescence staining experiments. YL and QL assisted with data analysis and interpretation. All the authors approved the manuscript.

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Correspondence to Qian Luo or Keqiang Ye.

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Qian, Z., Li, B., Meng, X. et al. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer’s disease in mice. Neuropsychopharmacol. 49, 620–630 (2024). https://doi.org/10.1038/s41386-023-01774-2

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