Considering the importance of NAD+ in energy metabolism, DNA repair and transcriptional regulation, maintaining intracellular NAD+ reserves emerges as a major therapeutic target for the treatment of several age-related degenerative diseases, including Alzheimer's disease (Belenky et al., 2007). In particular, increased nuclear NAD+ biosynthesis and consequent activation of SIRT1 has been shown to protect mouse neurons from mechanical and chemical injury (Bedalov and Simon, 2004). More importantly it was shown that NAD+ administration restored myelin and neuro-regeneration by activating spinal cord resident stem cells in an experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis (Tullius et al. 2014).
Overexpression of several enzymes of the NAD+ salvage pathway, including nicotinate phosphoribosyltransferase (PNC1) and nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) have been shown to extend lifespan in rat models by activating SIRT1 and promoting p53 deacetylation (van der Veer et al., 2007; Porcu and Chiarugi, 2005; Arraki et al., 2004; Berger et al., 2004; Bedalov and Simon, 2004). As 1:1 stoichiometry exists between the intracellular NAD+ content and sirtuin-mediated deacetylation (Grozinger and Schreiber, 2002), promotion of NAD+ anabolism appears as an important therapeutic target for promoting sirtuin function in neuronal cells during periods of repeated oxidative stress observed in Alzheimer's disease.
Increased NMNAT1 activity has also been shown to protect against axonal degeneration in Wallerian degeneration slow (Wlds) mice (Arraki et al., 2004). Exogenous administration of NAD+ prior to axotomy also delayed axonal degeneration, but to a lesser extent in NMNAT1 expressed mice, further indicating the importance of maintaining intracellular NAD+ pools as a preventive measure against axonal degradation (Arraki et al., 2004; Bedalov and Simon, 2004). In the absence of exogenous NAD+, PARP inhibition increased the survival of dorsal root ganglion cultures following mechanical injury. No protective effect on Wlds mice was observed following PARP inhibition in the presence of exogenous NAD+ (Arraki et al., 2004; Bedalov and Simon, 2004). This suggests that adequate intracellular NAD+ levels are essential for neuronal survival.
Axonopathy is a critical feature of several neurodegenerative diseases and often precede the death of neuronal bodies in AD (Raff et al., 2002). As axonal deficits are central to the patient’s neurological disability, therapies that prevent axonal degradation are of great therapeutic importance for treating AD.
Changes in intracellular NAD+ levels may also affect gene expression (Bedalov and Simon, 2004). Increased SIRT1 activity in fibroblasts, and most likely neurons, have been shown to alter gene expression by targeting several transcription factors including p53 (Vaziri et al., 2001; Luo et al., 2001), forkhead-box (FOXO) transcription family (Brunet et al., 2004; Motta et al., 2004), and NF-κB (Yeung et al., 2004). As SIRT1 activity responds to increased intracellular NAD+ levels, it is possible that enhanced NAD+ levels can induce several protective factors that will delay neuronal degeneration (Pallas etal., 2008). On the other hand, impaired SIRT1 activity due to PARP mediated NAD+ depletion can promote p53, FOXO and Bax activities which sensitize cells to apoptosis (Pillai et al., 2005). Therefore, drugs that promote SIRT1 activity are highly likely to reduce further neurodegeneration in AD.