Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.

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: Shilpy Dixit, Alexandra Bernardo, Jennifer Michelle Walker, John Andrew Kennard, Grace Youngeun Kim, Eric Sean Kessler, Fiona Edith Harrison
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 4 Pg. 570-81 (Apr 15 2015) ISSN: 1948-7193 [Electronic] United States
• PMID: 25642732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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