Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway

Jiunn Tay Lee, Jan Xu, Jin Moo Lee, Grace Ku, Xianlin Han, Ding I. Yang, Shawei Chen, Chung Y. Hsu

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

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-incluced 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.

Original languageEnglish
Pages (from-to)123-131
Number of pages9
JournalJournal of Cell Biology
Volume164
Issue number1
DOIs
Publication statusPublished - Jan 2004

    Fingerprint

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Cell death
  • Oxidative stress
  • White matter

ASJC Scopus subject areas

  • Cell Biology

Cite this

Lee, J. T., Xu, J., Lee, J. M., Ku, G., Han, X., Yang, D. I., Chen, S., & Hsu, C. Y. (2004). Amyloid-β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. Journal of Cell Biology, 164(1), 123-131. https://doi.org/10.1083/jcb.200307017