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.
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.
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DOI：
10.1016/j.neurobiolaging.2012.12.005
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发表时间：
2013-06
影响因子：
4.2
通讯作者：
Pasinetti GM
中科院分区：
文献类型：
--
作者：
Gong B;Pan Y;Vempati P;Zhao W;Knable L;Ho L;Wang J;Sastre M;Ono K;Sauve AA;Pasinetti GM
烟酰胺腺嘌呤二核苷酸（NAD+）是一种参与线粒体电子传递链中氧化还原活性的辅酶，已被鉴定为延长寿命效应的关键调节剂，并且NAD+表达的激活与阿尔茨海默病（AD）中β-淀粉样蛋白（Aβ）毒性的降低有关。烟酰胺核苷（NR）是一种NAD+前体，可促进脑内过氧化物酶体增殖物激活受体-γ共激活因子1（PGC）-1α的表达。有证据表明，PGC-1α是Aβ生成的关键调节因子，因为它影响β-分泌酶（BACE 1）的降解。在本研究中，我们检验了在AD小鼠模型中NR治疗可通过激活PGC-1α介导的BACE 1降解来减轻Aβ毒性的假设。使用Tg 2576 AD小鼠模型，使用体内行为分析、生物化学测定、小发夹RNA（shRNA）基因沉默和电生理记录，我们发现（1）用250 mg/kg/天的NR饮食治疗Tg 2576小鼠3个月，显著减轻了Tg 2576小鼠的认知恶化，并与稳态NAD+水平的增加相一致。（2）将NR应用于海马切片（10 µM）4小时，消除了Tg 2576小鼠CA 1区记录的长时程增强缺陷;（3）NR处理促进了Tg 2576小鼠脑中PGC-1α的表达，与BACE 1降解增强和Aβ产生减少一致。进一步的体外研究证实，NR处理降低了Tg 2576胚胎原代神经元培养物中BACE 1蛋白含量，其中BACE 1降解被PGC-1α-shRNA基因沉默所阻止;（4）NR处理和PGC-1α过表达增强了BACE 1泛素化和蛋白酶体降解。我们的研究表明，NR饮食治疗可能有利于AD认知功能和突触可塑性，部分通过促进PGC-1α介导的BACE 1泛素化和降解，从而防止大脑中Aβ的产生。
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 (Aβ) toxicity in Alzheimer’s disease (AD). Nicotinamide riboside (NR) is a NAD+ precursor, it promotes peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α expression in the brain. Evidence has shown that PGC-1α is a crucial regulator of Aβ generation because it affects β-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Aβ toxicity through the activation of PGC-1α-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 µM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1α expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Aβ 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-1α-shRNA gene silencing; and (4) NR treatment and PGC-1α overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, inpart by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.
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影响因子：
7.8
作者：
Gong B;Chen F;Pan Y;Arrieta-Cruz I;Yoshida Y;Haroutunian V;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
5.7
作者：
Herholz, K;Salmon, E;Heiss, WD
通讯作者：
Heiss, WD
影响因子：
11.4
作者：
Kim, Dohoon;Nguyen, Minh Dang;Tsai, Li-Huei
通讯作者：
Tsai, Li-Huei
影响因子：
3.9
作者：
La Piana, G;Marzulli, D;Lofrumento, NE
通讯作者：
Lofrumento, NE
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P