OREGON STATE UNIVERSITY
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Fiona Harrison, PhDAssistant Professor, Department of Medicine |
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| Abstract: Alzheimer’s disease is considered a disease of accelerated aging, and it is likely that pathogenic processes begin decades prior to changes in brain atrophy and cognitive decline are detected in clinic. Seizures are an important shared pathological feature of several neurodegenerative diseases that can dramatically increase cognitive decline by triggering apoptosis and cell death in hippocampus and cortical regions critical for learning and memory. Damage can occur even in the absence of large or observable seizures. Ascorbic acid (ascorbate, vitamin C) deficiency may contribute directly to the neurodegenerative changes that accompany seizures via the glutamate uptake-ascorbic acid release exchange mechanism in astrocytes. Low brain ascorbate altered expression of several genes involved in glutamate transport in the hippocampus, most notably GLT-1. Ascorbate deficient mice and mice carrying familial Alzheimer’s disease mutations (APPSWE/PSEN1dE9) are more sensitive than wild-type controls to kainic acid-induced seizures, even at very low doses. Accelerated and prolonged response patterns were observed in both EEG and behavioral studies. Upregulation of GLT-1, protected against acute kainic acid-induced immobility, but only in mice with adequate ascorbate levels. Even a single, very mild seizure negatively impacted learning and memory in the water-maze in APPSWE/PSEN1dE9 mice compared to wild-type controls. Together these studies support the role of ascorbate deficiency in increased seizure susceptibility, which may be particularly relevant in Alzheimer’s disease. | |