Sex-specific alterations in NAD+ metabolism in 3xTg Alzheimer's disease mouse brain assessed by quantitative targeted LC-MS

Autor: Tony Teav, Vera van der Velpen, Julijana Ivanisevic, Hector Gallart-Ayala, Vanille Maillard, Jean-Yves Chatton, Nadia Rosenberg
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
LC‐MS
brain
Mice
Transgenic
Nicotinamide adenine dinucleotide
Alzheimer Disease/metabolism
Animals
Chromatography
High Pressure Liquid/methods
Encephalitis/metabolism
Female
Humans
Kynurenic Acid/metabolism
Kynurenine/metabolism
Metabolome
Mice
NAD/metabolism
Neuroprotection
Nicotinamide Mononucleotide/metabolism
Sex Characteristics
Tandem Mass Spectrometry/methods
3xTg AD mouse model
Alzheimer's disease
LC-MS
NAD+ metabolism
targeted metabolomics
Kynurenic Acid
Biochemistry
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Kynurenic acid
Alzheimer Disease
Tandem Mass Spectrometry
Internal medicine
medicine
Chromatography
High Pressure Liquid
Kynurenine
Nicotinamide Mononucleotide
Nicotinamide mononucleotide
Nicotinamide
Chemistry
Neurodegeneration
Original Articles
medicine.disease
NAD
030104 developmental biology
Endocrinology
Encephalitis
Original Article
NAD+ kinase
030217 neurology & neurosurgery
Zdroj: Journal of Neurochemistry
Journal of neurochemistry, vol. 159, no. 2, pp. 378-388
ISSN: 1471-4159
Popis: Levels of nicotinamide adenine dinucleotide (NAD+) are known to decline with age and have been associated with impaired mitochondrial function leading to neurodegeneration, a key facet of Alzheimer's disease (AD). NAD+synthesis is sustained via tryptophan‐kynurenine (Trp‐Kyn) pathway as de novo synthesis route, and salvage pathways dependent on the availability of nicotinic acid and nicotinamide. While being currently investigated as a multifactorial disease with a strong metabolic component, AD remains without curative treatment and important sex differences were reported in relation to disease onset and progression. The aim of this study was to reveal the potential deregulation of NAD+metabolism in AD with the direct analysis of NAD+precursors in the mouse brain tissue (wild type (WT) versus triple transgenic (3xTg) AD), using a sex‐balanced design. To this end, we developed a quantitative liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method, which allowed for the measurement of the full spectrum of NAD+precursors and intermediates in all three pathways. In brain tissue of mice with developed AD symptoms, a decrease in kynurenine (Kyn) versus increase in kynurenic acid (KA) levels were observed in both sexes with a significantly higher increment of KA in males. These alterations in Trp‐Kyn pathway might be a consequence of neuroinflammation and a compensatory production of neuroprotective kynurenic acid. In the NAD+ salvage pathway, significantly lower levels of nicotinamide mononucleotide (NMN) were measured in the AD brain of males and females. Depletion of NMN implies the deregulation of salvage pathway critical for maintaining optimal NAD+ levels and mitochondrial and neuronal function.
Depletion of nicotinamide adenine dinucleotide (NAD+) pool was associated with impaired energy metabolism leading to neurodegeneration in Alzheimer's disease (AD), among others. However, the metabolic alterations related to the onset of this impairment remain poorly understood. We explored the changes in the NAD+ metabolism of the triple transgenic (3xTg) AD mouse brain compared to wild type, using a quantitative and highly specific liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) approach. Significant sex‐specific changes in the concentrations of metabolites implicated in de novo NAD+ synthesis and NAD+ salvage pathways were observed in the brain tissue of mice with AD pathology.
Databáze: OpenAIRE
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