ß-amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices

Accumulated evidence indicates that amyloid beta (Abeta) peptides, by interacting with the central glutamatergic system, can lead to degeneration of neurons associated with Alzheimer's disease (AD) pathology. However, very little is currently known about the role of Abeta peptides in the regulation of glutamatergic function in the normal brain. Given the evidence that Abeta peptides are produced constitutively in the normal brain, we investigated the possible association of amyloid precursor protein (APP)-containing neurons with the vesicular glutamatergic transporter-1 (VGluT1) and measured the effects of various Abeta peptides on endogenous glutamate release from adult rat brain slices. Our results showed that VGluT1 immunoreactivity is localized in close apposition to APP neurons, and that exogenous Abeta(1-40), in a dose-dependent (10(-12) to 10(-7)M) manner potently increased K(+)-evoked glutamate release from hippocampal slices. This effect was observed with other Abeta peptides such as Abeta(1-42), Abeta(1-28) and Abeta(25-35), but not with the reverse Abeta(1-40) or Abeta(25-35) sequences. Tetrodotoxin failed to alter the effects of Abeta(1-40) on glutamate release, which suggests the lack of involvement of voltage-dependent Na(+) channels. In addition to the hippocampus, Abeta(1-40) was found to potentiate K(+)-evoked glutamate release from cortical slices, whereas in the striatum the effect did not reach significant levels. These results demonstrate that physiological concentrations of Abeta peptides can regulate the release of glutamate by acting on glutamatergic terminals. Additionally, the evidence that selected regions of the brain are sensitive to Abeta peptides suggests a potential link between the deposition of Abeta and the preferential vulnerability of brain regions observed in AD pathology.