Alzheimer's disease is the most common dementia in aging humans, but its etiology is poorly understood. There is consensus that it relates in part to the toxicity and deposition of beta-amyloid fragments of the amyloid precursor protein. A key finding of beta-amyloid toxicity, even early in the clinical course of the disease, is oxidant stress. This manifests as lipid peroxidation and DNA damage in select cortical areas, followed by neuronal cell death. It follows that antioxidants, and particularly antioxidant vitamins such as ascorbic acid and alpha-tocopherol, should delay or prevent oxidant damage associated with beta-amyloid toxicity. However, this hypothesis has received little study. We propose to test it at the level of cultured neuronal cells and in animal models of Alzheimer's disease. Since neurons have the highest ascorbate content of any cell in the body, and since ascorbate is important as both a neuromodulator and antioxidant, we will focus on its role in preventing oxidant injury to cortical neurons.
The first aim uses cultured SHSY5Y neurons to establish mechanisms of ascorbate uptake and recycling, to test whether ascorbate prevents lipid peroxidation and spares alpha-tocopherol, and to determine whether intracellular ascorbate either lessens beta-amyloid-induced oxidant stress or modifies beta-amyloid secretion.
The second aim assesses the role of oxidant stress in the tissue damage and memory deficits in transgenic mice carrying mutations in key proteins implicated in human Alzheimer's disease. We expect to find that oxidant stress in these animals decreases cortical neuron concentrations of ascorbate, and that ascorbate supplements slow progression of cognitive defects by reversing local """"""""scurvy."""""""" We will also crossbreed the transgenic mouse model of Alzheimer's disease with a knockout mouse that cannot synthesize ascorbate. If ascorbate prevents neuronal cell oxidant damage, moderate ascorbate deficiency due to dietary restriction should hasten the onset and worsen the severity of oxidant stress and cognitive deficits. In the third aim, we will use cortical neurons cultured from neonatal transgenic mice to determine at the cell level the mechanisms by which antioxidant vitamins lessen lipid peroxidative damage. If antioxidant vitamins ameliorate toxicity in cell and animal models of Alzheimer's disease, then oxidant stress is involved in disease progression, and antioxidant vitamin supplements may be beneficial.
|May, James M (2012) Vitamin C transport and its role in the central nervous system. Subcell Biochem 56:85-103|
|Harrison, F E; May, J M; McDonald, M P (2010) Vitamin C deficiency increases basal exploratory activity but decreases scopolamine-induced activity in APP/PSEN1 transgenic mice. Pharmacol Biochem Behav 94:543-52|
|Harrison, F E; Hosseini, A H; Dawes, S M et al. (2009) Ascorbic acid attenuates scopolamine-induced spatial learning deficits in the water maze. Behav Brain Res 205:550-8|
|Harrison, F E; Hosseini, A H; McDonald, M P et al. (2009) Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice. Pharmacol Biochem Behav 93:443-50|
|Harrison, F E; Allard, J; Bixler, R et al. (2009) Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci 12:203-18|
|Harrison, Fiona E; Yu, Sarah S; Van Den Bossche, Kristen L et al. (2008) Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. J Neurochem 106:1198-208|
|Qiu, Shenfeng; Li, Liying; Weeber, Edwin J et al. (2007) Ascorbate transport by primary cultured neurons and its role in neuronal function and protection against excitotoxicity. J Neurosci Res 85:1046-56|
|May, James M; Li, Liying; Hayslett, Kendra et al. (2006) Ascorbate transport and recycling by SH-SY5Y neuroblastoma cells: response to glutamate toxicity. Neurochem Res 31:785-94|
|Harrison, Fiona E; Reiserer, Randall S; Tomarken, Andrew J et al. (2006) Spatial and nonspatial escape strategies in the Barnes maze. Learn Mem 13:809-19|
|Huang, Junjun; May, James M (2006) Ascorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by beta-amyloid. Brain Res 1097:52-8|