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Characterization of the toxic mechanism triggered by Alzheimer's amyloid‐β peptides via p75 neurotrophin receptor in neuronal hybrid cells

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 nontransfected 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 Gαo, 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. © 2003 Wiley‐Liss, Inc.