THE EFFECT OF A SECRETED FORM OF BETA-AMYLOID-PRECURSOR PROTEIN ON INTRACELLULAR CA2-NEURONS( INCREASE IN RAT CULTURED HIPPOCAMPAL)

1 The effects of secreted forms of beta-amyloid-precursor proteins (AP P(S)S) on the intracellular Ca2+ concentration ([Ca2+](i)) were invest igated in rat cultured hippocampal neurones. APP695(S), a secretory fo rm of APP695, attenuated the increase in [Ca2+](i) evoked by glutamate . In addition, APP695(S) itself evoked an increase in [Ca2+](i) in 1 o r 2 day-cultured hippocampal cells, but not in 7 to 13 day-cultured ce lls. 2 Eighty-one percent of neurones which were immunocytochemically positive for microtubule-associated protein 2 responded to APP695(S) w ith 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 el evation in inositol-1,4,5-trisphosphate (IP3) in a concentration-depen dent manner from 100 to 500 ng ml(-1). In the presence of extracellula r Ca2+, APP695(S) caused a transient rise in [Ca2+](i) followed by a s ustained phase at high [Ca2+](i), suggesting Ca2+ entry from the extra cellular space. 4 The [Ca2+](i) elevation was mimicked by amino termin al peptides of APP(S), but not by carboxy terminal peptides. 5 These r esults taken together suggest that APP695(S) induces an increase in [C a2+](i) in hippocampal neurones through an IP3-dependent mechanism tha t changes according to the stage of development.