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Caractérisation des effets protecteurs du NAD+ et du Nicotinamide Riboside lors de la dégénérescence axonale dans le système nerveux central : Implications dans les processus neurodégénératifs

Abstract : Synaptic and axonal degeneration (AxD) are major events in neurodegenerative diseases. Levels of NAD+, an important coenzyme for axonal integrity, are strongly reduced in different degeneration models so enhancing cellular NAD+ is one of the numerous therapeutic strategies against neuronal pathologies. Nicotinamide riboside (NR) is a good NAD+ precursor as it has already been shown to delay AxD in peripheral nervous system (PNS) and extracellular NAD+ conversion to NR was previously described in cell lines and in PNS. During my thesis project, we analyzed the role of NR metabolism to prevent degeneration processes in cortical neurons. Using an excitotoxicity model developed in microfluidic devices, we showed for the first time that both NAD+ and NR delay AxD in cortical neurons, with a more potent effect for NR. We confirm this differential effect in an in vivo ischemic model. Moreover, NR effect is mainly restricted to the axonal compartment and intracellular NAD+ depletion is reverted after NR application, suggesting that axonal integrity is totally dependent on NAD+ local metabolism. Furthermore, in a complete NAD+ depletion paradigm, NAD+ and NR have surprisingly the same strong effect, protecting equally neuronal death and AxD. Examination of the extracellular pathway suggest that NAD+ conversion to NR is limited in excitotoxicity but effective in the NAD+ depletion model. These results reveal that NR and NAD+ metabolism depend on the neurotoxic paradigm. Our results demonstrate that NR has a strong and local neuroprotective effect on AxD in several neurotoxic processes. These findings open new therapeutic strategies to prevent neurodegenerative diseases.
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Pauline Magda Marie Vaur. Caractérisation des effets protecteurs du NAD+ et du Nicotinamide Riboside lors de la dégénérescence axonale dans le système nerveux central : Implications dans les processus neurodégénératifs. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2016. Français. ⟨NNT : 2016PA066594⟩. ⟨tel-01889321⟩

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