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Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.
ACS Chem Neurosci. 2015 Apr 15; 6(4):570-81.AC

Abstract

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. These 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.

Authors+Show Affiliations

†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States. ‡Program in Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States. ‡Program in Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, United States.†Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25642732

Citation

Dixit, Shilpy, et al. "Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice." ACS Chemical Neuroscience, vol. 6, no. 4, 2015, pp. 570-81.
Dixit S, Bernardo A, Walker JM, et al. Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice. ACS Chem Neurosci. 2015;6(4):570-81.
Dixit, S., Bernardo, A., Walker, J. M., Kennard, J. A., Kim, G. Y., Kessler, E. S., & Harrison, F. E. (2015). Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice. ACS Chemical Neuroscience, 6(4), 570-81. https://doi.org/10.1021/cn500308h
Dixit S, et al. Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice. ACS Chem Neurosci. 2015 Apr 15;6(4):570-81. PubMed PMID: 25642732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice. AU - Dixit,Shilpy, AU - Bernardo,Alexandra, AU - Walker,Jennifer Michelle, AU - Kennard,John Andrew, AU - Kim,Grace Youngeun, AU - Kessler,Eric Sean, AU - Harrison,Fiona Edith, Y1 - 2015/02/12/ PY - 2015/2/3/entrez PY - 2015/2/3/pubmed PY - 2016/1/5/medline KW - Alzheimer’s disease KW - Vitamin C KW - amyloid KW - cognition KW - mouse models KW - oxidative stress SP - 570 EP - 81 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 6 IS - 4 N2 - 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. These 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. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/25642732/Vitamin_C_deficiency_in_the_brain_impairs_cognition_increases_amyloid_accumulation_and_deposition_and_oxidative_stress_in_APP/PSEN1_and_normally_aging_mice_ L2 - https://doi.org/10.1021/cn500308h DB - PRIME DP - Unbound Medicine ER -