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<p>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD<sup>+</sup> levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD<sup>+</sup> regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD<sup>+</sup> via control of the NAD<sup>+</sup>-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD<sup>+</sup> levels through a distinct pathway involving NFIL3-dependent suppression of the NAD<sup>+</sup>-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD<sup>+</sup> levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD<sup>+</sup> and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD<sup>+</sup> in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα–NFIL3–CD38 pathway controlling brain NAD<sup>+</sup> metabolism and neurodegeneration.</p>

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REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月1日

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  • Jiyeon Lee,
  • Ryeonghwa Kang,
  • Sohui Park,
  • Ibrahim O. Saliu,
  • Minsoo Son,
  • Jaymie R. Voorhees,
  • Julie M. Dimitry,
  • Elsa I. Quillin,
  • Lauren N. Woodie,
  • Brian V. Lananna,
  • Li Gan,
  • Young-Ah Goo,
  • Guoyan Zhao,
  • Mitchell A. Lazar,
  • Thomas P. Burris,
  • Erik S. Musiek

摘要

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα–NFIL3–CD38 pathway controlling brain NAD+ metabolism and neurodegeneration.