Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-β peptides (Aβ). Aβ binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Aβ causes cell death in neuronal hybrid cells transfected with p75NTR, but not in non-transfected cells, and that p75NTRL401K cannot mediate Aβ neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein α subunits in the presence of PTX and identified that Gα o, but not Gαi, proteins are involved in p75NTR-mediated Aβ neurotoxicity. Further investigation suggested that Aβ neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Aβ neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.
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