THE CA2-AMYLOID PEPTIDE-25-35 IN CULTURED HIPPOCAMPAL-NEURONS RESULTSFROM NETWORK EXCITATION( INFLUX INDUCED BY BETA)

Although a neurotoxic role has been postulated for the beta-amyloid pr otein (beta AP), which accumulates in brain tissues in Alzheimer's dis ease, a precise mechanism underlying this toxicity has not been identi fied. The peptide fragment consisting of amino acid residues 25 throug h 35 (beta AP25-35), in particular, has been reported to be toxic in c ultured neurons. We report that beta AP25-35, applied to rat hippocamp al neurons in culture, caused reversible and repeatable increases in t he intracellular Ca2+ concentration ([Ca2+](i)), as measured by fura 2 fluorimetry. Furthermore, beta AP25-35 induced bursts of excitatory p otentials and action potential firing in individual neurons studied wi th whole cell current clamp recordings. The beta AP25-35-induced [Ca2](i) elevations and electrical activity were enhanced by removal of ex tracellular Mg2+, and they could be blocked by tetrodotoxin, by non-N- methyl-D-aspartate (NMDA) and NMDA glutamate receptor antagonists, and by the L-type Ca2+ channel antagonist nimodipine. Similar responses o f bursts of action potentials and [Ca2+]i increases were evoked by bet a AP1-40. Responses to beta AP25-35 were not prevented by pretreatment with pertussis toxin. Excitatory responses and [Ca2+](i) elevations w ere not observed in cerebellar neuron cultures in which inhibitory syn apses predominate. Although the effects of beta AP25-35 depended on th e activation of glutamatergic synapses, there was no enhancement of ka inate- or NMDA-induced currents by beta AP25-35 in voltage-clamp studi es. We conclude that beta AP25-35 enhances excitatory activity in glut amatergic synaptic networks, causing excitatory potentials and Ca2+ in flux. This property may explain the toxicity of beta AP25-35. (C) 1995 John Wiley & Sons, Inc.