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

Abstract

1. The effects of secreted forms of β-amyloid-precursor proteins (APP^Ss) 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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