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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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DOI

  • Yujun Hou, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Sofie Lautrup, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Stephanie Cordonnier, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Yue Wang, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
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  • Deborah L Croteau, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Eduardo Zavala, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Yongqing Zhang, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
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  • Kanako Moritoh, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
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  • Jennifer F O'Connell, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
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  • Beverly A Baptiste, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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  • Tinna V Stevnsner
  • Mark P Mattson, Johns Hopkins University
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  • Vilhelm A Bohr, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; vbohr@nih.gov., Danish Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.

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.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences
Vol/bind115
Nummer8
Sider (fra-til)E1876-E1885
Antal sider10
ISSN0027-8424
DOI
StatusUdgivet - 20 feb. 2018

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