Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models

NEUROBIOLOGY OF AGING

卷:34

Article

Gong, Bing¹  Pan, Yong¹  Vempati, Prashant¹  Zhao, Wei¹  Knable, Lindsay¹  Ho, Lap¹  Wang, Jun¹  Sastre, Magdalena³  Ono, Kenjiro¹  Sauve, Anthony A.⁴  Pasinetti, Giulio M.^1,2 

[1] Mt Sinai Sch Med, Dept Neurol, Ctr Excellence Novel Approaches Neurotherapeut, New York, NY 10029 USA

[2] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA

[3] Univ London Imperial Coll Sci Technol & Med, Div Brain Sci, London, England

[4] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA

关键词: Nicotinamide riboside;    Alzheimer's disease;    beta-secretase (BACE1);    Promotes peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1 (PGC)-1 alpha;    Ubiquitin-proteasome system;    Mitochondrial metabolism;    Synaptic plasticity;    Long-term potentiation;   

DOI  :  10.1016/j.neurobiolaging.2012.12.005

来源: Elsevier

【 摘 要 】

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 (A beta) toxicity in Alzheimer's disease (AD). Nicotinamide riboside (NR) is a NAD(+) precursor, it promotes peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC)-1 alpha expression in the brain. Evidence has shown that PGC-1 alpha is a crucial regulator of A beta 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 A beta toxicity through the activation of PGC-1 alpha-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 mu M) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1 alpha expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of A beta 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-1 alpha-shRNA gene silencing; and (4) NR treatment and PGC-1 alpha 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-1 alpha-mediated BACE1 ubiquitination and degradation, thus preventing A beta production in the brain. (C) 2013 Elsevier Inc. All rights reserved.

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