Oligomeric forms of β-amyloid (Aβ(42)) peptides associated with Alzheimer's disease (AD) disrupt cellular Ca(2+) regulation by liberating Ca(2+) into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular Aβ by imaging Ca(2+) responses to injections of Aβ oligomers into Xenopus oocytes. Two types of signal were observed: (1) local, "channel-like" transients dependent on extracellular Ca(2+) influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; and (2) local transients and global Ca(2+) waves, resembling Ca(2+) puffs and waves mediated by inositol trisphosphate (IP(3)). The latter responses were suppressed by antagonists of the IP(3) receptor (caffeine and heparin), pretreatment with the G(i)(o)-protein inhibitor pertussis toxin, and pretreatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP(3) production and consequent liberation of Ca(2+) from the endoplasmic reticulum by intracellular Aβ oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP(3) receptor/channels.