NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency
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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DOI：
10.1073/pnas.1718819115
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发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Bohr, Vilhelm A.
中科院分区：
文献类型：
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作者：
Hou, Yujun;Lautrup, Sofie;Bohr, Vilhelm A.
新的研究结果表明，受损的细胞生物能量学和DNA修复有助于阿尔茨海默病（AD）的发病机制，但它们在疾病定义病理学中的作用尚不清楚。我们开发了一种DNA修复缺陷型3xTgAD/Pol β（+/-）小鼠，其加剧了人类AD的主要特征，包括磷酸化Tau（pTau）病理、突触功能障碍、神经元死亡和认知障碍。在这里，我们报告了3xTgAD/Pol β（+/-）小鼠具有降低的脑NAD（+）/NADH比率，表明脑能量代谢受损，其通过烟酰胺核苷（NR）治疗而正常化。NR减轻了3xTgAD和3xTgAD/Pol β（+/-）小鼠中的pTau病理学，但对淀粉样蛋白β肽（A β）积累没有影响。NR处理的3xTgAD/Pol β（+/-）小鼠表现出海马神经元的DNA损伤、神经炎症和凋亡减少，以及脑中SIRT 3活性增加。NR在多项行为测试中改善了认知功能，并恢复了3xTgAD小鼠和3xTgAD/Po β（+/-）小鼠的海马突触可塑性。一般而言，3xTgAD/Pol β（+/-）小鼠中基因型之间的缺陷和NR的益处大于3xTgAD小鼠。我们的研究结果表明，细胞NAD（+）耗竭上游的神经炎症，pTau，DNA损伤，突触功能障碍，和神经元变性在AD中的关键作用。因此，支持神经元NAD（+）水平的干预措施具有治疗AD的潜力。
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/Pol beta(+/-) 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/Pol beta(+/-) 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/Pol beta(+/-) mice but had no impact on amyloid beta peptide (A beta) accumulation. NR-treated 3xTgAD/Pol beta(+/-) 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/Po beta(+/-) mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Pol beta(+/-) 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.