Discussion

This study for the first time mechanistically explored the effects of NR on the attenuation of amyloid toxicity, improves cognitive function, and synaptic plasticity in AD mouse models. We for the first time demonstrated that the effects of NR are associated with the promotion of PGC-1α function and the ubiquitin proteasome system. The latter 2 have been indicated to play important roles in AD pathogenesis, and PGC-1α has been especially indicated in diabetes-related metabolism deterioration and aging-related dementia.
It has been shown that the effects of NAD on increasing life span have been linked with the activation of Sir1, Sir2, and further activation of PGC-1α expression, consequently affecting mitochondrial metabolism. NR is a NAD precursor. Evidence shows that extra-cellular NR application could increase intracellular NAD levels through glutamine-dependent NAD(+) synthetase (Qns) 1-independent and Nrk1-dependent pathways (Bieganowski and Brenner, 2004). Our data shows that treatment with NR in Tg2576 mice improves synaptic plasticity and behavioral function and is coincident with the increase in the NAD+ and PGC-1α levels, suggesting that the NR protective effects might be linked to the PGC-1α-regulated reduction of Aβ. Silencing PGC-1α abolished the effects of NR on the BACE1 degradation, further supporting this hypothesis.
Recently, evidence showed that BACE1 posttranslational degradation is a potential novel link in PGC-1α mediated protection against AD amyloid neuropathology (Gong et al., 2010; Katsouri et al., 2011; Kwak et al., 2011). BACE1 is a key secretase involved in the processing of APP, ultimately resulting in generation of amyloidogenic Aβ peptides. Here, we found that PGC-1α plays a important role in enhancing BACE1 degradation through mechanisms influencing UPS-mediated responses as NR does, suggesting that NR might also affect the UPS system through the regulation of PGC-1α. Thus, our study for the first time demonstrates this novel feature that NR promotes PGC-1α expression and BACE1 degradation in mechanisms associated with APP processing and AD β-amyloidosis in the brain.
Cerebral glucose hypometabolism has been associated with progression of AD dementia (Henneberg and Hoyer, 1995; Herholz et al., 2002) and positron emission tomography studies demonstrated that glucose utilization is reduced markedly in the brain of mild cognitive impairment and early stage AD (Jagust et al., 1991; Minoshima et al., 1995), which is associated with abnormal mitochondrial function. In recent genome-wide DNA microarray studies from our laboratory (Qin et al., 2009), we found that, among other genes involved in energy metabolism in the brain and other peripheral organs, PGC-1α expression is decreased significantly in the AD brain as part of the progression of AD dementia. Consistent with this evidence, we reported that PGC-1α expression is decreased in AD brain (Gong et al., 2010; Qin et al., 2009), as we recently found in the brains of the Tg2576 mouse model of AD neuropathology and cognitive deterioration. Based on this evidence, in this study, we continued exploring mechanistically the potential role of PGC-1α in mechanisms associated with energy metabolism in AD pathogenesis. Coincidently, the mitochondrial metabolism-related genes such as the Citrate synthase gene in tricarboxylic acid cycle genes (Srivastava et al., 2007), aconitase (Marmolino et al., 2010), pyruvate metabolism gene, pyruvate dehydrogenase kinase 3 (Sugden and Holness, 2003), cytochrome c subunit Vic (Szuplewski and Terracol, 2001), phosphoglycerate kinase (Fan et al., 2012), and glucose phosphate isomerase 1 (Morizot and Siciliano, 1982) were affected by the treatment of NR, which is possibly through the regulation of PGC-1α expression. On the other hand, NR has direct effects on the mitochondrial membrane, to prevent membrane depolarization during oxidation stress conditions, because the membrane potential is essential for the adenosine triphosphate (ATP) synthesis (Halestrap et al., 1997; La Piana et al., 2003; Woodfield et al., 1997).
In summary, our study suggested that the effects of NR on the reduction of Aβ toxicity through the alterations of PGC-1α expression, and the activation of UPS-regulated BACE1 degradation, also have indirect protective effects on mitochondrial metabolism through promotion of PGC-1α-mediated mitochondrial gene expression besides the reported NR direct effects on mitochondrial membrane protection. Our study provides a novel aspect of a potential application of NR in AD treatment.

Acknowledgements

The studies described here were supported in part from a grant from the Veterans Administration by the US National Institutes of Health grants to G.M.P. and by grant from Alzheimer’s Association (IIRG-08-89354) to B.G. The authors thank Dr Ottavio Arancio (Columbia University) for his advice on the reported electrophysiological recording and thank Ms. Amanda Bilski for assisting in preparation of the manuscript.

References