Amyloid beta peptide (25-35) inhibits Na+-dependent glutamate uptake in rat hippocampal astrocyte cultures

Large numbers of neuritic plaques surrounded by reactive astrocytes are characteristic of Alzheimer's disease (AD), There is a large body of research supporting a causal role for the amyloid beta peptide (A beta), a main constituent of these plaques, in the neuropathology of AD. Several hypotheses have been proposed to explain the toxicity of A beta including free radical injury and excito-toxicity. It has been reported that treatment of neuronal/ astrocytic cultures with A beta increases the vulnerability of neurons to glutamate-induced cell death, One mechanism that may explain this finding is inhibition of the astrocyte glutamate transporter by A beta. The aim of the current study was to determine if A beta s inhibit astrocyte glutamate uptake and if this inhibition involves free radical damage to the transporter/astrocytes. We have previously reported that A beta can generate free radicals, and this radical production was correlated with the oxidation of neurons in culture and inhibition of astrocyte glutamate uptake. In the present study, A beta (25-35) significantly inhibited L-glutamate uptake in rat hippocampal astrocyte cultures and this inhibition was prevented by the antioxidant Trolox, Decreases in astrocyte function, in particular L-glutamate uptake, may contribute to neuronal degeneration such as that seen in AD, These results lead to a revised excitotoxicity/free radical hypothesis of A beta toxicity involving astrocytes.