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¹ Center for the Study of Nervous System Injury, Department of Neurology
² Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110
³ Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China
⁴ Taipei Medical University, Taipei 110, Taiwan, Republic of China

Address correspondence to Chung Y. Hsu, 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. Tel.: (314) 362-3304. Fax: (314) 362-9462. email: hsuc{at}neuro.wustl.edu

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

Key Words: Alzheimer's disease; apoptosis; cell death; oxidative stress; white matter

Abbreviations used in this paper: 3-OMe-SM, 3-O-methyl-sphingomyelin; Aß, amyloid-ß peptide; AD, Alzheimer's disease; aSMase, acidic sphingomyelinase; bSMase, bacterial sphingomyelinase; BSO, buthionine sulfoximine; DEM, diethyl maleate; ESI/MS, electrospray ionization/mass spectrometry; GSH, glutathione; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC, N-acetylcysteine; nSMase, neutral sphingomyelinase; NOE, N-oleoyl-ethanolamine; OLG, oligodendrocyte; PLP, proteolipid protein.

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