Secreted Forms of β-Amyloid Precursor Protein Protect Hippocampal Neurons against Amyloid β-Peptide-Induced Oxidative Injury

Alternative processing of the β-amyloid precursor protein (βAPP) can result in liberation of either secreted forms of βAPP (App^ss), which may play roles in neuronal plasticity and survival, or amyloid β-peptide (Aβ), which can be neurotoxic. In rat hippocampal cell cultures Aβ1-40 caused a time- and concentration-dependent reduction in neuronal survival. App^s695 and App^s751 significantly reduced Aβ-induced injury in a concentration-dependent manner. Aβ caused an elevation of intracellular calcium levels ([Ca²⁺]_i) which was significantly attenuated by App^ss. Aβ also caused induction of reactive oxygen species (measured using the oxidation-sensitive fluorescent dye 2,7-dichlorofluorescin) which was also attenuated by App^ss. Aβ-induced neurotoxicity and elevations of [Ca²⁺]_i were attenuated by vitamin E, suggesting the involvement of free radicals in Aβ-induced loss of calcium homeostasis and neuronal injury. The App^ss protected neurons against oxidative injury caused by exposure to iron. Taken together, the data indicate that Aβ kills neurons by causing free radical production and increased [Ca²⁺]_i. App^ss can protect neurons against such free radical- and Ca²⁺-mediated injury. These findings support the hypothesis that altered processing of βAPP contributes to neuronal injury in Alzheimer's disease.