Glucose deprivation elicits neurofibrillary tangle-like antigenic changes in hippocampal neurons: prevention by NGF and bFGF

Abstract

A decrement in glucose utilization in brain was previously demonstrated in Alzheimer's disease (AD) and this abnormality has been proposed to play a role in the process of neuronal degeneration. We now report that glucose deprivation in cultured hippocampal neurons can result in antigenic alterations similar to those seen in AD neurofibrillary tangles (NFT) and, ultimately, cell death. Hypoglycemia caused an increase in neuronal immunoreactivity toward tau and ubiquitin antibodies. The antigenic alterations resulted from hypoglycemia-induced elevations in intracellular calcium levels as measured using the calcium indicator dye fura-2. The increased intraneuronal calcium levels, increased tau and ubiquitin immunoreactivities, and neuronal damage resulted from influx through the plasma membrane since they were not observed when cells were incubated in calcium-deficient medium. Neuronal damage and NFT-like antigenic changes were completely prevented by nerve growth factor (NGF) and basic fibroblast growth factor (bFGF), but not by epidermal growth factor (EGF). NGF and bFGF, but not EGF, prevented the aberrant rise in intracellular calcium levels that normally resulted from glucose deprivation. These data are consistent with the possibility that reduced glucose availability to neurons may contribute to the neuronal degeneration that occurs in AD. They also suggest that growth factors may normally protect neurons against hypoglycemic damage.