Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.
Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.
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DOI：
10.1021/cn500308h
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发表时间：
2015-04-15
影响因子：
5
通讯作者：
Harrison, Fiona Edith
中科院分区：
文献类型：
--
作者：
Dixit, Shilpy;Bernardo, Alexandra;Walker, Jennifer Michelle;Kennard, John Andrew;Kim, Grace Youngeun;Kessler, Eric Sean;Harrison, Fiona Edith
亚临床维生素C缺乏症在许多人群中很普遍，但它在阿尔茨海默病和正常衰老中的作用还没有得到充分的研究。在目前的研究中，我们通过将APP/PSEN1+双基因小鼠与SVCT2+/−杂合敲除小鼠杂交，减少了APPsWE/PSEN1deltaE9阿尔茨海默病小鼠模型中的脑维生素C，后者具有较少的钠依赖维生素C转运体，是神经元维生素C运输所需的。Svct2+/−小鼠在5个月和12个月龄时的旋转棒任务表现都不如同窝小鼠。SVCT2+/−和APP/PSEN1+小鼠以及SVCT2+/−APP/PSEN1+组合基因小鼠在多项认知能力测试(嗅觉记忆任务、Y迷宫交替、条件性恐惧、Morris水迷宫)中也受到损害。在年轻小鼠中，与野生型对照相比，低维生素C(SVCT2+/−)和APP/PSEN1突变都增加了大脑皮层氧化应激(丙二醛、蛋白质羰基、F2-异前列腺素)，并降低了总谷胱甘肽。Svct2+/−小鼠的Aβ1-42含量增加，Aβ1-42/1-40比值升高。到14个月龄时，各组之间的氧化应激水平相似，但与脑维生素C正常的APP/β+小鼠相比，SVCT2+/−APP/PSEN1+小鼠的海马区和皮质中有更多的淀粉样斑块沉积。数据表明，即使是中度的细胞内维生素C缺乏也在加速淀粉样蛋白的发病中发挥重要作用，特别是在疾病发展的早期阶段，这些影响可能是由氧化应激途径调节的。
Subclinical vitamin C deficiency is widespread in many populations, but its role in both Alzheimer’s disease and normal aging is understudied. In the present study we decreased brain vitamin C in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer’s disease, by crossing APP/PSEN1+ bigenic mice with SVCT2+/− heterozygous knockout mice, which have lower numbers of the sodium-dependent vitamin C transporter required for neuronal vitamin C transport. SVCT2+/− mice performed less well on the rotarod task at both 5 and 12 months of age compared to littermates. SVCT2+/− and APP/PSEN1+, mice, and the combination genotype SVCT2+/−APP/PSEN1+, were also impaired on multiple tests of cognitive ability (olfactory memory task, Y-maze alternation, conditioned fear, Morris water maze). In younger mice, both low vitamin C (SVCT2+/−) and APP/PSEN1 mutations increased brain cortex oxidative stress (malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased total glutathione compared to wild-type controls. SVCT2+/− mice also had increased amounts of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/1-40 ratio. By 14 months of age, oxidative stress levels were similar among groups, but there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2+/−APP/PSEN1+ mice compared to APP/PSEN1+ mice with normal brain vitamin C. The data suggest that even moderate intracellular vitamin C deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that these effects are likely modulated by oxidative stress pathways.
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影响因子：
2.4
作者：
Chung, JA;Cummings, JL
通讯作者：
Cummings, JL
影响因子：
3.6
作者：
Harrison, F. E.;Hosseini, A. H.;May, J. M.
通讯作者：
May, J. M.
DOI：
10.1111/j.1601-183x.2011.00762.x
发表时间：
2012-04
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Chen Y;Curran CP;Nebert DW;Patel KV;Williams MT;Vorhees CV
通讯作者：
Vorhees CV
影响因子：
2.6
作者：
Conti, Marta Zaffira;Vicini-Chilovi, Barbara;Rozzini, Luca
通讯作者：
Rozzini, Luca
影响因子：
2.5
作者：
Buckman, Laura B.;Thompson, Misty M.;Moreno, Heidi N.;Ellacott, Kate L. J.
通讯作者：
Ellacott, Kate L. J.