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

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

doi:10.1073/pnas.1718819115

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

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^*

^*Corresponding author for this work

128 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	8
Pages (from-to)	E1876-E1885
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1718819115
Publication status	Published - 2018

Keywords

Aging
Alzheimer’s disease
DNA repair
NAD supplementation
Nicotinamide riboside

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D. L., Zavala, E., Zhang, Y., Moritoh, K., O’Connell, J. F., Baptiste, B. A., Stevnsner, T. V., Mattson, M. P., & Bohr, V. A. (2018). NAD⁺ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proceedings of the National Academy of Sciences of the United States of America, 115(8), E1876-E1885. https://doi.org/10.1073/pnas.1718819115

NAD⁺ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. / Hou, Yujun; Lautrup, Sofie; Cordonnier, Stephanie et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 8, 2018, p. E1876-E1885.

Research output: Contribution to journal › Journal article › Research › peer-review

Hou, Y, Lautrup, S, Cordonnier, S, Wang, Y, Croteau, DL, Zavala, E, Zhang, Y, Moritoh, K, O’Connell, JF, Baptiste, BA, Stevnsner, TV, Mattson, MP & Bohr, VA 2018, 'NAD⁺ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 8, pp. E1876-E1885. https://doi.org/10.1073/pnas.1718819115

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title = "NAD+ supplementation normalizes key Alzheimer{\textquoteright}s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency",

abstract = "Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer{\textquoteright}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 = "Aging, Alzheimer{\textquoteright}s disease, DNA repair, NAD supplementation, Nicotinamide riboside",

author = "Yujun Hou and Sofie Lautrup and Stephanie Cordonnier and Yue Wang and Croteau, {Deborah L.} and Eduardo Zavala and Yongqing Zhang and Kanako Moritoh and O{\textquoteright}Connell, {Jennifer F.} and Baptiste, {Beverly A.} and Stevnsner, {Tinna V.} and Mattson, {Mark P.} and Bohr, {Vilhelm A.}",

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T1 - NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

AU - Hou, Yujun

AU - Lautrup, Sofie

AU - Cordonnier, Stephanie

AU - Wang, Yue

AU - Croteau, Deborah L.

AU - Zavala, Eduardo

AU - Zhang, Yongqing

AU - Moritoh, Kanako

AU - O’Connell, Jennifer F.

AU - Baptiste, Beverly A.

AU - Stevnsner, Tinna V.

AU - Mattson, Mark P.

AU - Bohr, Vilhelm A.

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N2 - 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.

AB - 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.

KW - Aging

KW - Alzheimer’s disease

KW - DNA repair

KW - NAD supplementation

KW - Nicotinamide riboside

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JF - Proceedings of the National Academy of Sciences of the United States of America

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