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Many synapses contain two types of receptors – integrins and N-methyl-D-aspartate (NMDA) receptors – that have been implicated in peptide internalization. The present studies tested if either class is involved in the uptake of the 42-residue form of amyloid beta peptide (Aβ1–42), an event hypothesized to be of importance in the development of Alzheimer’s disease. Cultured hippocampal slices were exposed to Aβ1–42 for 6 days in the presence or absence of soluble Gly-Arg-Gly-Asp-Ser-Pro, a peptide antagonist of Arg-Gly-Asp (RGD)-binding integrins, or the disintegrin echistatin. Aβ uptake, as assessed with immunocytochemistry, occurred in 42% of the slices incubated with Aβ peptide alone but in more than 80% of the slices co-treated with integrin antagonists. Uptake was also found in a broader range of hippocampal subfields in RGD-treated slices. Increased sequestration was accompanied by two characteristics of early stage Alzheimer’s disease: elevated concentrations of cathepsin D immunoreactivity and activation of microglia. The selective NMDA receptor antagonist D-(–)-2-amino-5-phosphonovalerate completely blocked internalization of Aβ, up-regulation of cathepsin D, and activation of microglia. Our results identify two classes of receptors that cooperatively regulate the internalization of Aβ1–42 and support the hypothesis that characteristic pathologies of Alzheimer’s disease occur once critical intraneuronal Aβ concentrations are reached. [Copyright &y& Elsevier]