β‐Amyloid peptide fragment 25–35 potentiates the calcium‐dependent release of excitatory amino acids from depolarized hippocampal slices

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Abstract
β-Amyloid protein (βAP) has been frequently associated with the neuropathology of Alzheimer's disease (AD), although the mechanisms by which it can induce neurodegeneration are still unknown. Some studies in hippocampal cultured neurons suggest that βAP, particularly its fragment 25ndash;35, may induce neural growth or render neurons more vulnerable to excitotoxic insults by a mechanism involving intracellular Ca2+ dyshomeostasis. We have studied the effect of fragment 25–35 on the release of endogenous amino acids from hippocampal slices of young adult (3–3.5-month-old) and aged (23–25-month-old) rats, under basal, K+ -depolarization, and post-depolarization conditions, in the presence and absence of Cat2+. In both young and aged tissue, the basal release of amino acids was not affected by the peptide. By contrast, 1-hr preincubation of slices from young animals with 10 μM 25–35 fragment resulted in a 140% increase of glutamate and aspartate release stimulated by K+ depolarization, compared with the control-stimulated release. These effects were strictly dependent on external Ca2+ Neither the K+ -stimulated release of γ-amino butyric acid (GABA) nor the release of glycine, glutamine, taurine, or alanine, which was not stimulated by high K+, were affected. Substance P and a scrambled sequence of the 25–35 fragment were without any effect per se, but substance P blocked the stimulatory effect of fragment 25–35 on glutamate and aspartate release. In slices from aged rats the basal release of glutamate was significantly higher (260%) than that in young tissue, and the K+ -induced release of both aspartate and glutamate was also higher. Fragment 25–35 also potentiated the K+ -induced release of these two amino acids, although to a lesser extent than in young tissue. These results indicate that glutamate is retained less by the aged hippocampus and that fragment 25–35 is able to augment the release of glutamate and aspartate under excitatory conditions, an effect that could be involved in the mechanisms of neurotoxicity of β-amyloid peptides.