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

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Yujun Hou, Sofie Lautrup, Stephanie Cordonnier, Yue Wang, Deborah L. Croteau, Eduardo Zavala, Yongqing Zhang, Kanako Moritoh, Jennifer F. O’Connell, Beverly A. Baptiste, Tinna V. Stevnsner, Mark P. Mattson, Vilhelm A. Bohr

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number8
Pages (from-to)E1876-E1885
ISSN0027-8424
DOIs
Publication statusPublished - 2018

    Research areas

  • Aging, Alzheimer’s disease, DNA repair, NAD supplementation, Nicotinamide riboside

ID: 193284585