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Cathepsin B modulates microglial migration and phagocytosis of amyloid β in Alzheimer’s disease through PI3K-Akt signaling

Neuropsychopharmacology volume 50, pages 640–650 (2025)Cite this article

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Abstract

The approval of anti-amyloid β (Aβ) monoclonal antibodies (lecanemab) for the treatment of patients with early preclinical stage of Alzheimer’s disease (AD) by the Food and Drug Administration, suggests the reliability and importance of brain Aβ clearance for AD therapy. Microglia are the main phagocytes that clear Aβ in the brain, but the underlying regulatory mechanism is unclear. Here, we investigate the critical role of cathepsin B (CatB) in modulating microglial Aβ clearance from mouse brain. Wild-type or CatB−/− mice were injected with Aβ into the hippocampus from 1 to 3 weeks. Mice were evaluated for cognitive change, Aβ metabolism, neuroinflammation. Microglia and neuron cultures were prepared to verify the in vivo results. The statistical analyses were performed by student’s t test, one-way ANOVA with a post hoc Tukey’s test using the GraphPad Prism software package. CatB deficiency significantly reduces Aβ clearance efficiency and aggravates mouse cognitive decline. Exogenous Aβ markedly increases CatB expression in activated microglia. Transcriptome analysis and in vitro cell culture experiments demonstrate that CatB is associated with gene clusters involved in migration, phagocytosis, and inflammation. In addition, transcriptome analysis and immunoblotting suggest that CatB modulates microglial Aβ clearance via PI3K-AKT activation. Our study unveils a previously unknown role of CatB in promoting microglial functionality during Aβ clearance.

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Fig. 1: CatB deficiency attenuated Aβ clearance in the mouse hippocampus.
Fig. 2: CatB deficiency attenuates microglial phagocytosis activity of Aβ.
Fig. 3: CatB inhibition attenuates microglial migration.
Fig. 4: CatB is involved in the PI3K-Akt pathway in microglia treated with Aβ.
Fig. 5: CatB-deficient microglia mediate toxic effects on neurons through insufficient Aβ clearance.

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All data supporting the conclusions of this article are included within the article and the additional files.

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Acknowledgements

We thank the Biological and Medical Engineering Core Facilities of Beijing Institute of Technology for supporting experimental equipment.

Funding

This work was supported by funding from National Natural Science Foundation of China (32070954, 82401130, 82101394, 82001167), Guangdong Provincial Department of Education General University Innovation Team Project (2024KCXTD016), Beijing Natural Science Foundation (7212066) and China Postdoctoral Science Foundation (2023MD734244).

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Authors and Affiliations

  1. Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China

    Muzhou Jiang, Yaping Pan & Li Lin

  2. Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China

    Muzhou Jiang, Wei Kong, Zhen Xie, Shuxuan Zhao, Xueshuai Kou, Simeng Zhang, Rui Meng, Hui Li, Zhenzhen Quan, Hong Qing & Junjun Ni

  3. Department of Implant Dentistry, Beijing Stomatological Hospital, Capital Medical University, Beijing, China

    Dan Zhao

  4. Department of Hematology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China

    Yue Zhou

  5. Beijing 171 Middle School, Beijing, China

    Yijie Xiong & Yanhui Li

  6. Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan

    Zhou Wu

  7. Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima, Japan

    Hiroshi Nakanishi

  8. Aerospace Medical Center, Aerospace Center Hospital, Beijing, China

    Juan Zhao

  9. Department of Biology, Shenzhen MSU-BIT University, Shenzhen, China

    Hui Li & Hong Qing

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Contributions

JN designed the research and wrote the manuscript; MJ performed most of the experiments and data analysis and wrote the manuscript. DZ, YZ, WK, and ZX performed part of the animal experiments. YX and YL conducted cell culture. SZ, XK, SZ, and RM analyzed data. YP, ZW, HN, JZ, HL, and ZQ provided the reagents. LL and HQ provided helpful suggestions to the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Li Lin or Junjun Ni.

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The author declares no competing interests.

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All animal care and experimental procedures were approved by the Institutional Animal Care and Use Committee of the Beijing Institute of Technology (BIT-EC-SCXK2018-0003-M-2021028) in conformity with the international guidelines on the ethics of animal experimentation.

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Jiang, M., Zhao, D., Zhou, Y. et al. Cathepsin B modulates microglial migration and phagocytosis of amyloid β in Alzheimer’s disease through PI3K-Akt signaling. Neuropsychopharmacol. 50, 640–650 (2025). https://doi.org/10.1038/s41386-024-01994-0

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