title: Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway.
abstract: Amyloid-beta peptide (Abeta) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Abeta induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Abeta-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Abeta and ceramide induced OLG death. In addition, Abeta activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Abeta 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 Abeta-induced OLG death. Glutathione (GSH) precursors inhibited Abeta activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Abeta-induced death. These results suggest that Abeta induces OLG death by activating the nSMase-ceramide cascade via an oxidative mechanism.
authors.affiliation: Center for the Study of Nervous System Injury, Dept. of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA.
authors.forename: Jiunn-Tay
authors.initials: JT
authors.lastname: Lee
authors.forename: Jan
authors.initials: J
authors.lastname: Xu
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
authors.forename: Grace
authors.initials: G
authors.lastname: Ku
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
authors.forename: Shawei
authors.initials: S
authors.lastname: Chen
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Hsu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D063388:Endocannabinoids; D004983:Ethanolamines / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009829:Oleic Acids; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D018874:Spheroids, Cellular / Q000166:cytology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013109:Sphingomyelins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D013109:Sphingomyelins; C033595:N-oleoylethanolamine; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione