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The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus

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Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesis pathway of the nicotinamide adenine dinucleotide (NAD). Both NAMPT and NAD progressively decline upon aging and neurodegenerative diseases. The depletion of NAMPT induces mitochondrial dysfunction in motor neurons and causes bioenergetic stress in neurons. However, the roles of NAMPT in hippocampus neurons need to be further studied. Using floxed Nampt (Namptflox/flox) mice, we knocked out Nampt specifically in the hippocampus CA1 neurons by injecting rAAV-hSyn-Cre-APRE-pA. The depletion of NAMPT in hippocampus neurons induced cognitive deficiency in mice. Nevertheless, no morphological change of hippocampus neurons was observed with immunofluorescent imaging. Under the transmission electron microscope, we observed mitochondrial swollen and mitochondrial number decreasing in the cell body and the neurites of hippocampus neurons. In addition, we found the intracellular Aβ (6E10) increased in the hippocampus CA1 region. The intensity of Aβ42 remained unchanged, but it tended to aggregate. The GFAP level, an astrocyte marker, and the Iba1 level, a microglia marker, significantly increased in the mouse hippocampus. In the primary cultured rat neurons, NAMPT inhibition by FK866 decreased the NAD level of neurons at > 10−9 M. FK866 dropped the mitochondrial membrane potential in the cell body of neurons at > 10−9 M and in the dendrite of neurons at > 10−8 M. FK866 decreased the number and shortened the length of branches of neurons at > 10−7 M. Together, likely due to the injury of mitochondria, the decline of NAMPT level can be a critical risk factor for neurodegeneration.

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Data Availability

The complete datasets in the current study are available from the corresponding author on request.

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Acknowledgements

We acknowledge Prof. Tang C for the critical reading of this manuscript.

Funding

The work was supported by the National Key R&D Program of China (2018YFA0507700), the National Natural Science Foundation of China (81971304 and 81573400), and the Zhejiang Provincial Natural Science Foundation of China (LY18H170001, LZ20H010001).

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Authors and Affiliations

  1. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China

    Chen Shen, Cong Chen, Tong Wang, Tong-Yao Gao, Min Zeng, Yun-Bi Lu & Wei-Ping Zhang

  2. Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China

    Chen Shen, Cong Chen, Tong Wang, Tong-Yao Gao, Min Zeng, Yun-Bi Lu & Wei-Ping Zhang

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  1. Chen Shen
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Contributions

WPZ and YBL designed the research, analyzed and interpreted data, and wrote the manuscript. CS performed the behavioral tests. CC performed the AAV injection and cultured the neurons. TW and TYG prepared and genotyped the mice. CS, CC, TW, TYG, and MZ prepared the materials, performed the experiments, and collected and preliminary analyzed the data together. All authors read and approved the final manuscript.

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Correspondence to Yun-Bi Lu or Wei-Ping Zhang.

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All animal experiments and animal husbandry were performed according to a protocol approved by the Ethics Committee of Laboratory Animal Care and Welfare, Zhejiang University School of Medicine, with the approval number ZJU2015-012–02.

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Shen, C., Chen, C., Wang, T. et al. The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus. Mol Neurobiol 60, 1267–1280 (2023). https://doi.org/10.1007/s12035-022-03142-5

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