Overproduction of the β-amyloid fragment 1–42 (Aβ1–42) is thought to contribute to synaptic dysfunction and neuronal death in Alzheimer's disease. Mounting evidence suggests that purinergic receptors play critical roles in synaptic plasticity and neuronal survival, but the potential involvement of these receptors in Aβ1–42-induced synaptic dysfunction and neuronal death has not been addressed. Here we report that Aβ1–42 promoted accumulation of the calcium-permeable purinergic receptor P2X4 in neurons. We also report evidence that Aβ1–42 induced a caspase-3-mediated cleavage of the receptor that slowed channel closure times and prevented agonist-induced internalization of the receptor. Molecular interference to reduce the expression of P2X4 in primary rodent neurons attenuated Aβ1–42-induced neuronal death while induced expression of P2X4 in a neuronal cell line that does not normally express P2-receptors enhanced the toxic effect of Aβ1–42. Together these findings suggest that Aβ1–42-induced synaptic dysfunction and neuronal death may involve perturbations in P2X4 purinergic receptors.