Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein

The β-amyloid precursor protein (βAPP) is a membrane-spanning glycoprotein that is the source of the β-amyloid peptide (βAP) which accumulates as senile plaques in the brains of patients with Alzheimer's disease. βAPP is normally processed such that a cleavage occurs within the βAP, liberating secreted forms of βAPP (APP^ss) from the cell. The neuronal functions of these forms are unknown. We now report that APP^ss have a potent neuroprotective action in cultured rat hippocampal and septal neurons and in human cortical neurons. APP^s₆₉₅ and APP^s₇₅₁ protected neurons against hypoglycemic damage, and the neuroprotection was abolished by antibodies to a specific region common to both APP^s₆₉₅ and APP^s₇₅₁. APP^ss caused a rapid and prolonged reduction in [Ca²⁺]₁ and prevented the rise in [Ca²⁺]_i that normally mediated hypoglycemic damage. APP^ss also protected neurons against glutamate neurotoxicity, effectively raising the excitotoxic threshold. APP^ss may normally play excitoprotective and neuromodulatory roles. Alternative processing of APP^ss in Alzheimer's disease may contribute to neuronal degeneration by compromising the normal function of APP^ss and by promoting the deposition of βAP.