The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus - PubMed (original) (raw)

. 2023 Mar;60(3):1267-1280.

doi: 10.1007/s12035-022-03142-5. Epub 2022 Nov 28.

Affiliations

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

Chen Shen et al. Mol Neurobiol. 2023 Mar.

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.

Keywords: Mitochondria homeostasis; NAD (nicotinamide adenine dinucleotide); NAMPT (nicotinamide phosphoribosyltransferase); Neurodegeneration.

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Zeng K, Yu X, Mahaman YAR, Wang JZ, Liu R, Li Y, Wang X (2022) Defective mitophagy and the etiopathogenesis of Alzheimer’s disease. Transl Neurodegener 11:32. https://doi.org/10.1186/s40035-022-00305-1 - DOI
    1. Yaku K, Okabe K, Nakagawa T (2018) NAD metabolism: implications in aging and longevity. Ageing Res Rev 47:1–17. https://doi.org/10.1016/j.arr.2018.05.006 - DOI
    1. Okabe K, Yaku K, Tobe K, Nakagawa T (2019) Implications of altered NAD metabolism in metabolic disorders. J Biomed Sci 26:34. https://doi.org/10.1186/s12929-019-0527-8 - DOI
    1. Clement J, Wong M, Poljak A, Sachdev P, Braidy N (2019) The plasma NAD(+) metabolome is dysregulated in “normal” aging. Rejuvenation Res 22:121–130. https://doi.org/10.1089/rej.2018.2077 - DOI
    1. Ralto KM, Rhee EP, Parikh SM (2020) NAD(+) homeostasis in renal health and disease. Nat Rev Nephrol 16:99–111. https://doi.org/10.1038/s41581-019-0216-6 - DOI

MeSH terms

Substances

Grants and funding

LinkOut - more resources