Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging

Alejandro Sánchez-Melgar,Mairena Martín,José Luis Albasanz,Mercè Pallàs

doi:10.3390/ijms21197300

Alejandro Sánchez-Melgar, Mairena Martín + Show 2 more

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https://doi.org/10.3390/ijms21197300

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Abstract

Adenosine is a neuromodulator that has been involved in aging and neurodegenerative diseases as Alzheimer’s disease (AD). In the present work, we analyzed the possible modulation of purine metabolites, 5’nucleotidase (5′NT) and adenosine deaminase (ADA) activities, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its phosphorylated form during aging in the cerebral cortex. Three murine models were used: senescence-accelerated mouse-resistant 1 (SAMR1, normal senescence), senescence-accelerated mouse-prone 8 (SAMP8, a model of AD), and the wild-type C57BL/6J (model of aging) mice strains. Glutamate and excitatory amino acid transporter 2 (EAAT2) levels were also measured in these animals. HPLC, Western blotting, and enzymatic activity evaluation were performed to this aim. 5′-Nucleotidase (5′NT) activity was decreased at six months and recovered at 12 months in SAMP8 while opposite effects were observed in SAMR1 at the same age, and no changes in C57BL/6J mice. ADA activity significantly decreased from 3 to 12 months in the SAMR1 mice strain, while a significant decrease from 6 to 12 months was observed in the SAMP8 mice strain. Regarding purine metabolites, xanthine and guanosine levels were increased at six months in SAMR1 without significant differences in SAMP8 mice. In C57BL/6J mice, inosine and xanthine were increased, while adenosine decreased, from 4 to 24 months. The AMPK level was decreased at six months in SAMP8 without significant changes nor in SAMR1 or C57BL/6J strains. Glutamate and EAAT2 levels were also modulated during aging. Our data show a different modulation of adenosine metabolism participants in the cerebral cortex of these animal models. Interestingly, the main differences between SAMR1 and SAMP8 mice were found at six months of age, SAMP8 being the most affected strain. As SAMP8 is an AD model, results suggest that adenosinergic metabolism is involved in the neurodegeneration of AD.

Highlights

Adenosine is a key regulator of the neurotransmission in the central nervous system operating through four receptors: A1, A2A, A2B, and A3
5 -nucleotidase (5 NT) catalyzes the formation of adenosine from adenosine monophosphate (AMP) [16], and adenosine deaminase is involved in the degradation of adenosine to inosine [17]
We found a slight increase in adenosine deaminase (ADA) activity from 4 to 24 months in the C57BL/6J mice strain, which could have contributed to the lower adenosine and higher inosine levels detected in old mice

Summary

Introduction

Adenosine is a key regulator of the neurotransmission in the central nervous system operating through four receptors: A1, A2A, A2B, and A3. These receptors belong to the G-protein coupled receptors (GPCRs) family, and activate (A2A, A2B) or inhibit (A1, A3) adenylyl cyclase enzyme, modulating intracellular cAMP levels. Many studies have revealed that adenosine receptors, mainly A1 and A2A, are strongly altered in neurodegenerative [4,5,6,7,8] and neuropsychiatric disorders [9,10,11]. 5 -nucleotidase (5 NT) catalyzes the formation of adenosine from adenosine monophosphate (AMP) [16], and adenosine deaminase is involved in the degradation of adenosine to inosine [17]

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