| First Author | Gong B | Year | 2013 |
| Journal | Neurobiol Aging | Volume | 34 |
| Issue | 6 | Pages | 1581-8 |
| PubMed ID | 23312803 | Mgi Jnum | J:203369 |
| Mgi Id | MGI:5526900 | Doi | 10.1016/j.neurobiolaging.2012.12.005 |
| Citation | Gong B, et al. (2013) Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging 34(6):1581-8 |
| abstractText | Nicotinamide adenine dinucleotide (NAD)(+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in beta-amyloid (Abeta) toxicity in Alzheimer's disease (AD). Nicotinamide riboside (NR) is a NAD(+) precursor, it promotes peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC)-1alpha expression in the brain. Evidence has shown that PGC-1alpha is a crucial regulator of Abeta generation because it affects beta-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Abeta toxicity through the activation of PGC-1alpha-mediated BACE1 degradation. Using the Tg2576 AD mouse model, using in vivo behavioral analyses, biochemistry assays, small hairpin RNA (shRNA) gene silencing and electrophysiological recording, we found (1) dietary treatment of Tg2576 mice with 250 mg/kg/day of NR for 3 months significantly attenuates cognitive deterioration in Tg2576 mice and coincides with an increase in the steady-state levels of NAD(+) in the cerebral cortex; (2) application of NR to hippocampal slices (10 muM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1alpha expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Abeta production in Tg2576 mice. Further in vitro studies confirmed that BACE1 protein content is decreased by NR treatment in primary neuronal cultures derived from Tg2576 embryos, in which BACE1 degradation was prevented by PGC-1alpha-shRNA gene silencing; and (4) NR treatment and PGC-1alpha overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, in part by promoting PGC-1alpha-mediated BACE1 ubiquitination and degradation, thus preventing Abeta production in the brain. |
