NAD + supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1876-E1885. doi: 10.1073/pnas.1718819115. Epub 2018 Feb 5.

Abstract

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/Polβ+/- mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/- mice have a 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/Polβ+/- mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ+/- mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/- mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ+/- 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 therapeutic potential for AD.

Keywords: Alzheimer’s disease; DNA repair; NAD supplementation; aging; nicotinamide riboside.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease*
  • Animals
  • Cognitive Dysfunction
  • DNA Damage
  • Disease Models, Animal*
  • Gene Expression Regulation / drug effects
  • Male
  • Mice
  • Mice, Transgenic
  • NAD / pharmacology*
  • Neurogenesis / drug effects
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism
  • Sirtuins / genetics
  • Sirtuins / metabolism
  • tau Proteins / metabolism

Substances

  • Sirt3 protein, mouse
  • tau Proteins
  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Sirt6 protein, mouse
  • Sirtuin 3
  • Sirtuins