Pathogenic interactions between altered cellular Ca2+ signaling and amyloid β in its different aggregation states have been extensively described in neurons (for review, see Demuro et al., 2010); however, the effects in astrocytes remain controversial. Here, we found that the [Ca2+]i rise caused by amyloid β1-42 oligomers was due to Ca2+ release from intracellular stores, because (i) it occurred in nominally Ca2+-free medium and (ii) [Ca2+]i increases were reduced in the presence of inhibitors of PLC, InsP3Rs, and RyRs. We also show that Ca2+ influx contributes to a late sustained Ca2+ response that is modulated by IP3 signaling but not by Ca2+ release through RyRs. Further experiments will be necessary to define the extracellular Ca2+ routes of amyloid β-induced Ca2+ response in astrocytes. Consistent with these results, previous observations have also suggested that the neurotoxic fragment of amyloid β (25–35) may activate intracellular Ca2+ release (Stix & Reiser, 1998). In contrast, other studies have shown that the full-length amyloid β-induced Ca2+ signaling is entirely dependent on Ca2+ influx from the extracellular space, through amyloid β inserts into the plasma membrane or by modulating the properties of existing Ca2+-permeable channels (Abramov et al., 2003, 2004); however, the source of Ca2+ was not precisely defined in these studies. These discrepancies may arise from different stimulation paradigms or different aggregation states of amyloid β peptides. Indeed, our findings indicate that the aggregation states of amyloid β differentially affect Ca2+ dysregulation in astrocytes, because only the oligomeric peptide, but not fibrillar and unaggregated amyloid, changes the intracellular Ca2+ levels. Similarly, oligomers, but not monomers or fibrils, increased intracellular free Ca2+ in neurons (Demuro et al., 2005) and oligomeric, fibrillar and monomeric species differentially affect neuronal viability (Dahlgren et al., 2002). In addition, here we demonstrate that amyloid β-induced Ca2+ signaling is dependent on PLC activation, suggesting that amyloid β oligomers could destabilize the membrane leading to PLC translocation (Hicks et al., 2008) or to activation of G protein-coupled receptors. However, selective blockade of metabotropic glutamate or purinergic receptors did not reduce the Ca2+ levels reached after amyloid β treatment, indicating that other alternative mechanisms may be involved in this signaling. Ca2+ signaling in astrocytes is central to astroglial functions (Araque, 2008); therefore, dysregulation of Ca2+ signaling in astrocytes is likely to affect the ability of astrocytes to function as integral components of the nervous system. Dysfunctional astroglial Ca2+ signaling is found in many pathological states, including epilepsy, ischemia and cortical spreading depression following stroke or traumatic brain injury (Nedergaard et al., 2010). Functional consequences of disturbed astrocytic Ca2+ homeostasis in AD begin to emerge (Vincent et al., 2010). Ca2+ signaling is disrupted in astrocytes of transgenic mouse models of AD (Kuchibhotla et al., 2009) and in cultured astrocytes exposed to Aβ peptides (Stix & Reiser, 1998; Abramov et al., 2003; Chow et al., 2010). Collectively, these studies indicate that soluble Aβ is potentially detrimental to astrocytic function.