EVIDENCE FOR EXCITOPROTECTIVE AND INTRANEURONAL CALCIUM-REGULATING ROLES FOR SECRETED FORMS OF THE BETA-AMYLOID PRECURSOR PROTEIN

The beta-amyloid precursor protein (betaAPP) is a membrane-spanning glycoprotein that is the source of the beta-amyloid peptide (betaAP) which accumulates as senile plaques in the brains of patients with Alzheimer's disease. BetaAPP is normally processed such that a cleavage occurs within the betaAP, liberating secreted forms of betaAPP (APP(S)s) from the cell. The neuronal functions of these forms are unknown. We now report that APP(S)s have a potent neuro-protective action in cultured rat hippocampal and septal neurons and in human cortical neurons. APP(S)695 and APP(S)751 protected neurons against hypoglycemic damage, and the neuroprotection was abolished by antibodies to a specific region common to both APP(S)695 and APP(S)751. APP(S)s caused a rapid and prolonged reduction in [Ca2+]i and prevented the rise in [Ca2+]i that normally mediated hypoglycemic damage. APP(S)s also protected neurons against glutamate neurotoxicity, effectively raising the excitotoxic threshold. APP(S)s may normally play excitoprotective and neuromodulatory roles. Alternative processing of APP(S)s in Alzheimer's disease may contribute to neuronal degeneration by compromising the normal function of APP(S)s and by promoting the deposition of betaAP.