Elsevier

Neurobiology of Aging

Volume 34, Issue 6, June 2013, Pages 1581-1588
Neurobiology of Aging

Regular article
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

https://doi.org/10.1016/j.neurobiolaging.2012.12.005Get rights and content

Abstract

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, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.

Introduction

Nicotinamide adenine dinucleotide (NAD)+ has been identified as a key regulator in the lifespan-extending effects of calorie restriction in a number of species. Numerous studies have suggested that NAD+ mediates multiple major biological processes, including calcium homeostasis, energy metabolism, mitochondrial functions, cell death, and aging in various tissues including brain. Increasing evidence has suggested that NAD+ might play important roles in metabolic processes in the brain, and has effects on brain functioning such as neurotransmission, learning, and memory. Recent studies have shown that the activation of NAD expression has been linked with a decrease in the amyloid toxicity in Alzheimer's disease (AD) animal models (Kim et al., 2007; Qin et al., 2006), in which it might relate to the interactions with the expression of peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α (Nemoto et al., 2005) and through the activation of neuronal NAD-dependent deacetylase sirtuin-1 (SIRT1) activation (Qin et al., 2006; Rodgers et al., 2005). It has been shown that during metabolic stress conditions such as the fasting state, hypoxia, NAD+ levels, and SIRT1 protein levels are increased, leading to deacetylation of PGC-1α, subsequently increasing the expression of PGC-1α, promoting gluconeogenic transcriptional program (Rodgers et al., 2005), consequently protecting the mitochondrial energy metabolism. Thus, the benefits of the NAD+ stimulating cell survival have raised the hope that using pharmacological agents to increase NAD+ concentrations might provide therapeutic benefits in delaying the onset and slowing the progression of AD dementia.

Nicotinamide riboside (NR) is a NAD precursor, which is converted to NAD through action of human NrK1 and NrK2 genes in the de novo fashion (Bieganowski and Brenner, 2004; Bieganowski et al., 2003). Evidence shows that NR treatment increases intracellular NAD+ concentration and improves NAD+-dependent activities in the cell by increasing silent mating-type information regulation 2 (Sir2)-dependent gene silencing and longevity via nicotinamide riboside kinase (NRK) 1-dependent NAD+ synthesis (Belenky et al., 2007). Thus it is possible that the exogenous application of NR is capable of promoting the biosynthesis of NAD, thus promoting the beneficial effects of NAD (Braidy et al., 2008). Excitingly, it has been reported that treatment with nicotinamide prevents cognition in AD transgenic mice via a mechanism involving sirtuin inhibition and reduction of tau phosphorylation (Green et al., 2008). However, the role of NR in the beta-amyloid (Aβ) deposition in AD brain is still not clear.

It has been shown that PGC-1α also plays an important role in energy metabolism by regulating mitochondrial function in different tissues. The expression of PGC-1 has been found significantly decreased in Alzheimer's brains, and it is involved in the Aβ pathological generation by affecting the processing of amyloid precursor protein (APP), at least partially through enhancing the α-secretase activity (Qin et al., 2009; Wu et al., 2006). Recently, our group and others reported that 1 of the mechanisms in which the PGC-1 decreases the Aβ burden is also involved in the regulation of the F-Box (FbX)2-E3-ligase-mediated β-secretase (BACE1) degradation (Gong et al., 2010; Katsouri et al., 2011) as it does in other E3 ligases in the ubiquitin system in other tissues. Encouraged by the effects of NAD on promoting the PGC-1 expression, in this study, we tested the hypothesis that exogenous treatment of NR might reduce the Aβ burden in AD brain via enhancing PGC-1α expression, which increases BACE1 ubiquitination, degradation, and improves mitochondrial metabolism. Our study provides a novel therapeutic strategy for the treatment of AD.

Section snippets

Animals

Tg2576 mice were crossed with PGC-1α−/− mice (Qin et al., 2009) and generated PGC-1α−/−/Tg2576 mice. Animals were backcrossed at least 10 generations onto normal C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME, USA). All experiments were approved by the Mount Sinai School of Medicine Animal Care committees.

Primary neuronal cell culture

Tg2576 mouse primary neuronal cell cultures were prepared from the brains of 14.5-day-old embryos bred from wild type C57BL/6 females crossed with Tg2576 males, as described previously (

NR treatment promotes cognition coincided with induction of PGC-1α

To assess if NR has any protective effects on cognitive function as we proposed, we first treated Tg2576 AD transgenic (APP) mice (Hsiao et al., 1996) (7–8-month-old) with 250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human) for 3 months via drinking water. We found that the NR treatment significantly improved cognitive performance of these mice in an object recognition test, which is a cognitive task to examine hippocampal- and cortical-dependent learning. This cognition function is

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

Disclosure statement

All authors have no potential conflicts of interest.

All experiments were approved by the Mount Sinai School of Medicine Animal Care committees.

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.

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    Current address: Department of Neurology and Neurobiology and Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

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