Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polb+/- mouse that exacerbates major features of human AD including pTau pathologies, synaptic dysfunction, neuronal death and cognitive impairment. Here we report that 3xTgAD/Polb+/- mice have reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polb+/- mice, but had no impact on Abeta accumulation. NR-treated 3xTgAD/Polb+/- mice exhibited reduced DNA damage, neuroinflammation, apoptosis of hippocampal neurons, and increased activity of SIRT3 in the brain. NR improves cognitive function in multiple behavioral tests, and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polb+/- mice. In general, the deficits and the benefits of NR were greater in 3xTgAD/Polb+/- mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have potential in AD.
Overall design
Wildtype (WT), Alzheimer's Disease triple transgenic (AD, 3xTgAD), Polymerase beta heterozygote (PolB, Polb+/-), and AD/PolB (ADP) mice were treated with vehicle or nicotinamide riboside (12mM) for six months (four biological replicates per group, using hippocampal and cortical tissues, for a total of 64 samples).
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