Although a neurotoxic role has been postulated for the β‐amyloid protein (βAP), which accumulates in brain tissues in Alzheimer's disease, a precise mechanism underlying this toxicity has not been identified. The peptide fragment consisting of amino acid residues 25 through 35 (βAP25‐35), in particular, has been reported to be toxic in cultured neurons. We report that βAP25‐35, applied to rat hippocampal neurons in culture, caused reversible and repeatable increases in the intracellular Ca2+ concentration ([Ca2+]i), as measured by fura 2 fluorimetry. Furthermore, βAP25‐35 induced bursts of excitatory potentials and action potential firing in individual neurons studied with whole cell current clamp recordings. The βAP25‐35–induced [Ca2+]i elevations and electrical activity were enhanced by removal of extracellular 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 of bursts of action potentials and [Ca2+]i increases were evoked by βAP1‐40. Responses to βAP25‐35 were not prevented by pretreatment with pertussis toxin. Excitatory responses and [Ca2+]i elevations were not observed in cerebellar neuron cultures in which inhibitory synapses predominate. Although the effects of βAP25‐35 depended on the activation of glutamatergic synapses, there was no enhancement of kainate‐ or NMDA‐induced currents by βAP25‐35 in voltage‐clamp studies. We conclude that βAP25‐35 enhances excitatory activity in glutamatergic synaptic networks, causing excitatory potentials and Ca2+ influx. This property may explain the toxicity of βAP25–35. © 1995 John Wiley & Sons, Inc.
- Alzheimer's disease
- glutamate receptors
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience