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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Refolo, Lorenzo
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Mi, Deborah J; Dixit, Shilpy; Warner, Timothy A et al. (2018) Altered glutamate clearance in ascorbate deficient mice increases seizure susceptibility and contributes to cognitive impairment in APP/PSEN1 mice. Neurobiol Aging 71:241-254
Yu, Hao; Harrison, Fiona Edith; Xia, Fen (2018) Altered DNA repair; an early pathogenic pathway in Alzheimer's disease and obesity. Sci Rep 8:5600
Sharif, N F; Korade, Z; Porter, N A et al. (2017) Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav 16:619-626
Dixit, Shilpy; Fessel, Joshua P; Harrison, Fiona E (2017) Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate. Free Radic Biol Med 112:515-523
Walker, Jennifer M; Dixit, Shilpy; Saulsberry, Anjelica C et al. (2017) Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, ?-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease. Neurobiol Dis 100:87-98
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
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
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

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