The effect of a secreted form of β-amyloid-precursor protein on intracellular Ca²⁺ increase in rat cultured hippocampal neurones

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.