Alternative processing of the β-amyloid precursor protein (βAPP) can result in liberation of either secreted forms of βAPP (Appss), 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. Apps695 and Apps751 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 Appss. Aβ also caused induction of reactive oxygen species (measured using the oxidation-sensitive fluorescent dye 2,7-dichlorofluorescin) which was also attenuated by Appss. 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 Appss 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. Appss 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.
ASJC Scopus subject areas