Fibrillar Amyloid- Peptides Kill Human Primary Neurons via NADPH Oxidase-mediated Activation of Neutral Sphingomyelinase

Alzheimer’s disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis. However, the mechanism behind neuronal apoptosis in the Alzheimer’s-diseased brain is poorly understood. This study underlines the importance of neutral sphingomyelinase in fibrillar A peptide-induced apoptosis and cell death in human primary neurons. A 1–42 peptides induced the activation of sphingomyelinases and the production of ceramide in neurons. Interestingly, neutral (N-SMase), but not acidic (A-SMase), sphingomyelinase was involved in A 1–42-mediated neuronal apoptosis and cell death. A 1–42-induced production of ceramide was redox-sensitive, as reactive oxygen species were involved in the activation of N-SMase but not ASMase. A 1–42 peptides induced the NADPH oxidasemediated production of superoxide radicals in neurons that was involved in the activation of N-SMase, but not A-SMase, via hydrogen peroxide. Consistently, superoxide radicals generated by hypoxanthine and xanthine oxidase also induced the activation of N-SMase, but not A-SMase, through a catalase-sensitive pathway. Furthermore, antisense knockdown of p22phox, a subunit of NADPH oxidase, inhibited A 1–42-induced neuronal apoptosis and cell death. These studies suggest that fibrillar A 1–42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NSMase-ceramide pathway.