Alzheimer's disease (AD) is associated with a build up of oxidative stress in addition to the classic neuropathological signs of amyloid plaques, neurofibrillary tangles and cell death. An adequate supply of antioxidants in the diet during the lifetime, and especially in at-risk populations may mitigate the risk of excess damage by oxidative stress, however, the exact roles of particular antioxidants have yet to be clarified. In the current application we propose to investigate the role of vitamin C (ascorbic acid;ASC) in the development of neuropathology and cognitive deficits in a mouse model of AD. Further we will investigate the therapeutic potential of ASC to treat memory impairments. ASC is transported across the choroid plexus and into neurons by the Sodium-dependent Vitamin C Transporter (SVCT2). The creation of new mouse lines that either lack, or carry additional copies of the SVCT2 permits us for the first time to investigate the effects of a long term decrease or increase in brain ASC level, by the same mechanism, and without risk of ill health due to scurvy. We will cross these mice with an established mouse model of AD, APP/PSEN1 mice, and investigate how differing ASC levels impact the development of learning and memory impairments and also concomitant neuropathological changes at early, mid-, and later stages of disease progression. We anticipate that these data will reinforce the necessity to promote adequate intake of ASC and other antioxidants throughout the life-span, but especially in at-risk individuals. More importantly the data will tell us how ASC interacts with disease pathology to offer this critical neuroprotection. Finally, we present evidence that ASC can act as a neuromodulator, and we propose to investigate the potential of ASC to act as a novel, acute treatment via interperitoneal, and intra-ventricular treatments. These data will provide evidence that ASC can be used as a non-toxic treatment to improve memory deficits in APP/PSEN1 mice, and to promote further investigation of their use in humans.

Public Health Relevance

This project is to study the relationship between vitamin C and oxidative stress in the aging brain and in Alzheimer's disease. It will provide clear evidence as to the role of vitamin C in Alzheimer neuropathology and associated learning and memory deficits. It will also investigate the potential for vitamin C administration via parenteral routes, as a new therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038739-04
Application #
8644779
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$287,519
Indirect Cost
$103,019
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Warner, Timothy A; Kang, Jing-Qiong; Kennard, John A et al. (2015) Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease. Epilepsy Res 110:20-5
Dixit, Shilpy; Bernardo, Alexandra; Walker, Jennifer Michelle et al. (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 Chem Neurosci 6:570-81
He, Xi-Biao; Kim, Mirang; Kim, Seon-Young et al. (2015) Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner. Stem Cells 33:1320-32
Walker, Jennifer M; Harrison, Fiona E (2015) Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer's Disease: Impacts on Cognitive Decline. Nutrients 7:7332-57
Harrison, Fiona E; Bowman, Gene L; Polidori, Maria Cristina (2014) Ascorbic acid and the brain: rationale for the use against cognitive decline. Nutrients 6:1752-81
Korade, Zeljka; Xu, Libin; Harrison, Fiona E et al. (2014) Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome. Biol Psychiatry 75:215-22
Kennard, John A; Harrison, Fiona E (2014) Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice. Behav Brain Res 264:34-42
Ward, Margaret S; Lamb, Jonathan; May, James M et al. (2013) Behavioral and monoamine changes following severe vitamin C deficiency. J Neurochem 124:363-75
May, James M; Harrison, Fiona E (2013) Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal 19:2068-83
Harrison, Fiona Edith; Best, Jennifer Lee; Meredith, Martha Elizabeth et al. (2012) Increased expression of SVCT2 in a new mouse model raises ascorbic acid in tissues and protects against paraquat-induced oxidative damage in lung. PLoS One 7:e35623

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