Nicotinamide Phosphoribosyltransferase May Be Involved in Age-Related Brain Diseases

Li-Ying Liu,Peng Huang,Wei-Ping Zhang,Yun-Bi Lu,Feng Wang,Er-Qing Wei,Xia-Yan Zhang,Gilles J Guillemin

doi:10.1371/journal.pone.0044933

Li-Ying Liu, Peng Huang + Show 6 more

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https://doi.org/10.1371/journal.pone.0044933

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Journal: PLoS ONE	Publication Date: Oct 11, 2012
Citations: 45	License type: CC BY 4.0

Affiliation: Zhejiang University, Zhejiang Chinese Medical University

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis, and can be found either intracellularly (iNAMPT) or extracellularly (eNAMPT). Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD) level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.

Highlights

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for synthesizing nicotinamide adenine dinucleotide (NAD) [1]
NAMPT can be found either intracellularly or extracellularly [8]. iNAMPT participates in the salvage pathway of NAD synthesis — NAD plays a vital role in energy metabolism, serving as a cofactor of histone deacetylase sirtuins, regulates cell death through poly(ADP-ribose) polymerase 1 (PARP-1) [9], linking iNAMPT to these important cellular processes [10]
We have found a region- and cell-specific change of NAMPT level upon aging — it decreased in brain while increases in serum; in brain, it increased in microglia but likely decreased in neuron

Summary

Introduction

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for synthesizing nicotinamide adenine dinucleotide (NAD) [1]. It is expressed in many different organs and tissues including brain [2,3], liver [4], bone marrow [5], skeletal muscle [6] and adipose tissue [7]. ENAMPT, mostly in the form of serum NAMPT, likely functions as a cytokine in circulation. It has been named pre-B cell enhancing factor (PBEF), as it was first cloned from human peripheral blood lymphocyte and could enhance B cell maturation [5]. Due to the scarcity of adenosine-triphosphate (ATP) in the extracellular space, the enzymatic activity of eNAMPT was poor under normal circumstances [11]

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