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Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer’s Disease-Type Pathology and Cognitive Deficits

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Abstract

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer’s disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82122023 and U22A20294).

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Zhi-Hao Liu, Jin-Cai He & Yan-Jiang Wang

  2. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China

    Zhi-Hao Liu, Yu-Di Bai, Zhong-Yuan Yu, Hui-Yun Li, Jie Liu, Cheng-Rong Tan, Gui-Hua Zeng, Yun-Feng Tu, Pu-Yang Sun, Yu-Juan Jia, Yan-Jiang Wang & Xian-Le Bu

  3. Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, 400042, China

    Zhi-Hao Liu, Yu-Di Bai, Zhong-Yuan Yu, Hui-Yun Li, Jie Liu, Cheng-Rong Tan, Gui-Hua Zeng, Yun-Feng Tu, Pu-Yang Sun, Yu-Juan Jia, Yan-Jiang Wang & Xian-Le Bu

  4. Institute of Brain and Intelligence, Third Military Medical University, Chongqing, 400042, China

    Yan-Jiang Wang & Xian-Le Bu

  5. State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400042, China

    Yan-Jiang Wang & Xian-Le Bu

  6. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 201200, China

    Yan-Jiang Wang

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  1. Zhi-Hao Liu
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Liu, ZH., Bai, YD., Yu, ZY. et al. Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer’s Disease-Type Pathology and Cognitive Deficits. Neurosci. Bull. 39, 1775–1788 (2023). https://doi.org/10.1007/s12264-023-01077-y

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