1. The effects of secreted forms of β-amyloid-precursor proteins (APP(s)s) on the intracellular Ca2+ concentration ([Ca2+](i)) were investigated in rat cultured hippocampal neurones. APP695(s), a secretory form of APP695, attenuated the increase in [Ca2+](i) evoked by glutamate. In addition, APP695(s) itself evoked an increase in [Ca2+](i) in 1 or 2 day-cultured hippocampal cells, but not in 7 to 13 day-cultured cells. 2. Eighty-one percent of neurones which were immunocytochemically positive for microtubule-associated protein 2 responded to APP695(s) with an increase in [Ca2+](i). 3. APP695(s) induced a transient rise in [Ca2+](i) even in the absence of extracellular Ca2+ and produced an elevation in inositol-1,4,5-trisphosphate (IP3) in a concentration-dependent manner from 100 to 500 ng ml-1. In the presence of extracellular Ca2+, APP695(s) caused a transient rise in [Ca2+](i) followed by a sustained phase at high [Ca2+](i), suggesting Ca2+ entry from the extracellular space. 4. The [Ca2+](i) elevation was mimicked by amino terminal peptides of APP(s), but not by carboxy terminal peptides. 5. These results taken together suggest that APP695(s) induces an increase in [Ca2+](i) in hippocampal neurones through an IP3-dependent mechanism that changes according to the stage of development.
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