Amyloid-β Peptide Induces Oligodendrocyte Death by Activating the Neutral Sphingomyelinase-Ceramide Pathway

• Published in: The Journal of cell biology Vol. 164; no. 1; pp. 123 - 131
• Main Authors: Lee, Jiunn-Tay, Xu, Jan, Lee, Jin-Moo, Ku, Grace, Han, Xianlin, Ding-I Yang, Chen, Shawei, Hsu, Chung Y.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.01.2004; The Rockefeller University Press
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Amyloids; Animals; Apoptosis; Cell death; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Cellular biology; Ceramides; Ceramides - metabolism; Ceramides - pharmacology; Cultured cells; Cytotoxicity; Endocannabinoids; Ethanolamines - pharmacology; Glutathione - metabolism; Lipids; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurons; Oleic Acids; Oligodendroglia - cytology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Rats; Signal Transduction - physiology; Spheroids, Cellular - cytology; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelins - pharmacology; Toxicity; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200307017

Amyloid-β peptide (Aβ) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Aβ induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Aβ-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Aβ and ceramide induced OLG death. In addition, Aβ activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Aβ cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death. Furthermore, nSMase inhibition by 3-O-methyl-sphingomyelin or by gene knockdown using antisense oligonucleotides attenuated Aβ-induced OLG death. Glutathione (GSH) precursors inhibited Aβ activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Aβ-induced death. These results suggest that Aβ induces OLG death by activating the nSMase-ceramide cascade via an oxidative mechanism.