Article ; Online: 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
2015 Volume 6, Issue 4, Page(s) 570–581
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 ... ...
| 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. |
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| MeSH term(s) | 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 |
| Chemical Substances | 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 (PQ6CK8PD0R) |
| Language | English |
| Publishing date | 2015-04-15 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ISSN | 1948-7193 |
| ISSN (online) | 1948-7193 |
| DOI | 10.1021/cn500308h |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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