Table 1.
A Summary of Laboratory Evidence of Linkages between NAD+ Depletion/Supplementation and Neurological Disorders
| Condition | NAD+ Precursor | Effects of Supplementation in Disease Models | Demonstrated in | References |
|---|---|---|---|---|
| Brain Aging | NR | ↑ UPRmt and prohibitins → ↑ proliferation of neural stem cells (NSCs) and muscle stem cells → ↑ neurogenesis → ↑ lifespan | 22- to 24-month-old C57BL/6J (400 mg/kg/day for 6 weeks) | Zhang et al., 2016 |
| NMN | ↑ NAD+ → ↑ SIRT1/SIRT2 → ↑ NSCs/progenitor cells likely via ↑ neurogenesis | 18-month-old C57BL/6 (300 mg/kg/day for 12 months), neurospheres (100 μM) | Stein and Imai, 2014 | |
| AD | NAM | ↑ SIRT1 expression, antioxidant levels and autophagy-lysosome clearance → ↑ oxidative stress resistance → ↑ mitochondrial function/integrity → ↓ Aβ and p-Tau → ↑ neuronal plasticity/cognitive function | 3xTgAD cultured cortical neurons (40 mg/kg/day for 8 months) | Liu et al., 2013 |
| ↑ p25/Cdk5 → ↓ p-Tau231 via degradation of p-Tau231 | 3xTgAD (200 mg/kg/day for 4 months) | Green et al., 2008 | ||
| ↑ acet. A-Tubulin, perhaps via SIRT2 inhibition → ↑ microtubule stability | ||||
| NR | ↑ NAD+ → ↑ SIRT3, SIRT6 and ↓ PARP1 + PAR due to ↓ DNA damage (γH2AX) → ↓ p-Tau, no effect on Aβ → ↑ neurogenesis, ↑ LTP and cognitive function, ↓ neuroinflammation (NLRP3, Caspase 3) | 3xTgAD and 3xTgAD/Polβ+/− (12 mM for 6 months) | Hou et al., 2018 | |
| ↑ NAD+ → ↑ PGC-1α (likely via SIRT1) → ↑ BACE1 degradation → ↓ Aβ → ↑ cognition | Tg2576 (250 mg/kg/day for 3 months), hippocampal slices from Tg2576 (10 μM) | Gong et al., 2013 | ||
| ↑ mitophagy and ↑ UPRmt → ↑ mitochondrial function → ↓ Aβ aggregation → ↑ fitness, memory, and lifespan | Aβ model of C. elegans, 3xTgAD mice, APP/PS1 mice, APP-SH-SY5Y cells (1 or 3 mM for worms and cells, 400 mg/kg/day for 10 weeks) | Sorrentino et al., 2017 | ||
| NMN | ↑ mitophagy → ↑ mitochondrial integrity → ↑ microglial function incl. phagocytosis → ↑ neuronal function | APP/PS1, 3xTgAD, Aβ1–42 and Tau models of C. elegans (5 mM) | Fang et al., 2019 | |
| CD38 KD | ↑ NAD+ → ↓ Aβ → ↑ cognition | APP/PS1 mice | Blacher et al., 2015 | |
| PD | NAM | ↑ mitochondrial function, ↓ oxidative stress → ↓ DNA damage and protein oxidation → ↑ motor function (Drosophila) | MPP+ induced cellular model (101 mg/L), α-syn transgenic Drosophila model (15 or 30 mg/100 g diet). | Jia et al., 2008 |
| ↑ NAD+ → ↑ mitochondrial function → ↑ neuroprotection → ↓ loss of dopaminergic neurons | parkin or pinkl mutant Drosophila (5 mM) | Lehmann et al., 2016, 2017 | ||
| NAD+ | ↑ NAD+ → ↑ sensitivity toward MeHg → ↓ MeHg-induced neuronal damage → ↑ DAergic neuron morophology and behavior | MeHg-treated C. elegans (1 mM) | Caito and Aschner, 2016 | |
| ALS | NR or NMN | in astrocytes: ↑ NAD+ → ↑ NADPH /↑ SIRT1, 3 and/or 6 → ↓ acet. of IDH2 / activation of Nrf2 → ↑ oxidative stress resistance → ↑ mitochondrial function → ↓ toxicity toward cocultured neurons | primary astrocytes from SOD1 mutant mice, astrocytes isolated post-mortem from spinal cord of ALS patients (5 mM) | Harlan etal., 2016, 2019 |
| HD | NAM | NAM was used as a HDAC inhibitor → ↑ acet. of mHtt → ↑ autophagic clearance of mHtt → reversed toxic effects of mHtt | HD C. elegans model (5 mM) | Jeong et al., 2009 |
| NAM was used as an HDAC/SIRT2 (Sir2) inhibitor → inhibition of Rpd3 and Sir2 → ↑ neuroprotection | Htt transgenic Drosophila (2 to 20 mM) | Pallos et al., 2008 | ||
| ↑ PGC-1α and ↑ BDNF → no effect on aggregation phenotyp, ↑ of motor functions | B6.HD6/1 mice (250 mg/kg for 12 weeks) | Hathorn et al., 2011 | ||
| NR | ↑ NAD+ → ↑ act. Of SIRT1/PGC-1α and SIRT3 → ↑ oxidative metabolism → ↑ neuroprotection → ↓ HD-related motor dysfunction and related pathways | STHdhQ111 cells, R6/2 and BACHD mouse models (unpublished data) | Unpublished data; Lloret and Beal, 2019 |
3xTgAD, triple transgenic Alzheimer’s disease mouse model; 3xTgAD/Polβ+/−, 3xTgAD heterozygous in DNA polymerase beta; Aβ, amyloid beta; acet, acetylated; act, activity; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; APP/PS1, mice containing human transgenes for both APP bearing the Swedish mutation and PSEN1 containing an L166P mutation; BACE1, beta-secretase; BDNF, brain-derived neurotrophic factor; Cdk5, cyclin-dependent kinase 5; Daergic, dopaminergic; HD, Huntington disease; HDAC, histone deacetylase; IDH2, isocitrate dehydrogenase 2; LTP, long-term potentiation; MeHg, methyl mercury; mHtt, mutant huntingtin; NAD+, nicotinamide adenine dinucleotide; NADPH, NAD phosphate; NAM, nicotinamide; NLRP3, NLR family pyrin domain-containing 3; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; Nrf2, nuclear factor erythroid 2-related factor 2; NSCs, neural progenitor cells; PAR, poly(ADP) ribosylation; PARP1, PAR polymerase 1; PD, Parkinson’s disease; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; p-Tau, phosphorylated Tau; Rpd3, histone deacetylase Rpd3; SIRT, Sirtuin; UPRmt, mitochondrial unfolded protein response; Tg2576, mice expressing the human APP (amyloid precursor protein) gene carrying the Swedish mutation.