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Precursors van Glutathion voorkomen dood van
hersencellen bij Alzheimer*
Jiunn-Tay Lee3, Jan Xu1,
Jin-Moo Lee1, Grace Ku1, Xianlin Han2, Ding-I
Yang1, Shawei Chen1 and Chung Y. Hsu1,4
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.
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. (2004)