Fibrillar Amyloid-β Peptides Kill Human Primary Neurons via NADPH Oxidase-mediated Activation of Neutral Sphingomyelinase: IMPLICATIONS FOR ALZHEIMER'S DISEASE

Arundhati Jana,Kalipada Pahan

doi:10.1074/jbc.m404635200

Arundhati Jana, Kalipada Pahan

Open Access

https://doi.org/10.1074/jbc.m404635200

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Abstract

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 Abeta peptide-induced apoptosis and cell death in human primary neurons. Abeta1-42 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 Abeta1-42-mediated neuronal apoptosis and cell death. Abeta1-42-induced production of ceramide was redox-sensitive, as reactive oxygen species were involved in the activation of N-SMase but not A-SMase. Abeta1-42 peptides induced the NADPH oxidase-mediated 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 Abeta1-42-induced neuronal apoptosis and cell death. These studies suggest that fibrillar Abeta1-42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NS-Mase-ceramide pathway.

Highlights

Alzheimer’s disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis
We show that the activation of neutral, but not acidic, sphingomyelinase plays the vital role in neuronal apoptosis and that NADPH oxidase-mediated superoxide production in neurons is responsible for A␤-induced activation of neutral sphingomyelinase
Fibrillar A␤1– 42 Peptides Induce the Production of Ceramide in Human Primary Neurons—Because the fibrillar form of A␤ is commonly found in the senile plaques in Alzheimer’s disease (AD) brains [1], we examined whether fibrillar A␤1– 42 is capable of inducing apoptosis in human primary neurons

Summary

Introduction

Alzheimer’s disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis. This study underlines the importance of neutral sphingomyelinase in fibrillar A␤ peptide-induced apoptosis and cell death in human primary neurons. Neutral (N-SMase), but not acidic (A-SMase), sphingomyelinase was involved in A␤1– 42-mediated neuronal apoptosis and cell death. 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. 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. We report that fibrillar A␤1– 42 peptides induce the activation of sphingomyelinases and the production of ceramide in human primary neurons. We show that the activation of neutral, but not acidic, sphingomyelinase plays the vital role in neuronal apoptosis and that NADPH oxidase-mediated superoxide production in neurons is responsible for A␤-induced activation of neutral sphingomyelinase

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