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. doi: 10.1021/cn500308h. Epub 2015 Feb 12.


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.

Keywords: Alzheimer’s disease; Vitamin C; amyloid; cognition; mouse models; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Anxiety / metabolism
  • Anxiety / pathology
  • Ascorbic Acid / metabolism
  • Ascorbic Acid Deficiency / metabolism*
  • Ascorbic Acid Deficiency / pathology
  • Ascorbic Acid Deficiency / psychology
  • Brain / metabolism*
  • Brain / pathology
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Disease Models, Animal
  • Female
  • Learning / physiology
  • Male
  • Memory / physiology
  • Mice, Transgenic
  • Motor Activity / physiology
  • Oxidative Stress / physiology*
  • Peptide Fragments / metabolism
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Sodium-Coupled Vitamin C Transporters / genetics
  • Sodium-Coupled Vitamin C Transporters / metabolism


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Slc23a2 protein, mouse
  • Sodium-Coupled Vitamin C Transporters
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Ascorbic Acid