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Title page for ETD etd-09252017-180743

Type of Document Dissertation
Author Dixit, Shilpy
URN etd-09252017-180743
Title Ascorbate Deficiency Accelerates Neuropathology in Alzheimer's Disease
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Christine Konradi, Ph.D. Committee Chair
Aaron Bowman, Ph.D. Committee Member
James May, M.D. Committee Member
Laura Dugan, M.D. Committee Member
  • Vitamin C
  • Alzheimers disease
  • Mitochondria
  • Gene expression
Date of Defense 2017-08-31
Availability unrestricted
Subclinical ascorbate deficiency is widespread in many populations, but its role in both Alzheimer’s disease and normal aging is understudied. We decreased brain ascorbate in the APPSWE/PSEN1deltaE9 mouse model of Alzheimer’s disease by crossing APP/PSEN1+ bigenic mice with SVCT2+/− heterozygous knockout mice, which have lower expression of the sodium-dependent vitamin C transporter required for neuronal ascorbate transport. At 6 months, SVCT2+/− and APP/PSEN1 mice and the combination genotype SVCT2+/−;APP/PSEN1 were impaired on multiple tests of cognitive ability and exhibited increased oxidative stress in the brain. Increased amyloid plaque burden was observed in SVCT2+/−;APP/PSEN1 mice compared to APP/PSEN1 mice at 14 months. At 4 months of age, during what is considered a prodromal stage in mouse models of Alzheimer’s disease, mitochondria isolated from SVCT2+/− and APP/PSEN1 mice showed disruptions in oxygen consumption and mitochondrial respiration with opposing directionality indicating that different pathways were being affected. Both groups had significant increases in the production of reactive oxygen species. Additionally, genes commonly associated with Alzheimer’s disease pathology and progression were up-regulated in SVCT2+/−;APP/PSEN1 mice and APP/PSEN1, with a greater magnitude of gene expression change in SVCT2+/−;APP/PSEN1 mice. Furthermore, 5-hydroxymethylcytosine levels, indicative of epigenetic modification, were significantly increased compared to wild type at 4 months. There were differing patterns of gene expression based on SVCT2+/− and APP/PSEN1 status, as well as with age, suggesting an age-related change in gene expression occurs earlier in APP/PSEN+ groups and is exacerbated in combination with ascorbate deficiency. These data support the hypothesis that even moderate ascorbate deficiency plays an important role in accelerating amyloid pathogenesis, particularly during early stages of disease development, and that oxidative stress pathways likely modulate these effects.

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