Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes.
There is growing recognition that white matter pathology is a common feature in Alzheimer's disease. We have previously reported that the amyloid beta peptide (Abeta) induces apoptosis in oligodendrocytes (OLG), via activation of neutral sphingomyelinase (nSMase) and resultant generation of ceramide. In the current study, we report that both Abeta and ceramide increased expression of the proapoptotic protein DP5/Hrk (DP5), and release of cytochrome C from mitochondria to cytoplasm in OLGs. We provide evidence that the Jun N-terminal kinase (JNK) signaling pathway mediates Abeta- and ceramide-induced apoptosis: Both Abeta and ceramide activated JNK phosphorylation, and subsequent AP-1 DNA binding activity; JNK siRNA decreased AP-1 DNA binding, DP5 expression and reduced cell death. Furthermore, inhibition of nSMase attenuated Abeta-induced JNK phosphorylation, AP-1 DNA binding activity, DP5 expression, and cytochrome C release. Collectively, these results suggest that Abeta-induced apoptosis involves the sequential activation of nSMase with ceramide generation, JNK activation, AP-1 DNA binding, and DP5 expression.
Chen
Shawei
S
Department of Neurology and the Hope Center for Neurological Disorders, Washington University, School of Medicine, St Louis, MO 63110, USA.
Lee
Jin-Moo
JM
Zeng
Chenbo
C
Chen
Hong
H
Hsu
Chung Y
CY
Xu
Jan
J
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002458:Cell Fractionation / Q000379:methods; D002467:Cell Nucleus / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000737:chemistry / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; C484585:Hrk protein, rat; C064769:N-acetylsphingosine; D009479:Neuropeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D018808:Transcription Factor AP-1; D048670:MAP Kinase Kinase 4; D013108:Sphingomyelin Phosphodiesterase; C022616:thiazolyl blue; D013110:Sphingosine