title: Beta-amyloid oligomers activate apoptotic BAK pore for cytochrome c release.
abstract: In Alzheimer's disease, cytochrome c-dependent apoptosis is a crucial pathway in neuronal cell death. Although beta-amyloid (Aβ) oligomers are known to be the neurotoxins responsible for neuronal cell death, the underlying mechanisms remain largely elusive. Here, we report that the oligomeric form of synthetic Aβ of 42 amino acids elicits death of HT-22 cells. But, when expression of a bcl-2 family protein BAK is suppressed by siRNA, Aβ oligomer-induced cell death was reduced. Furthermore, significant reduction of cytochrome c release was observed with mitochondria isolated from BAK siRNA-treated HT-22 cells. Our in vitro experiments demonstrate that Aβ oligomers bind to BAK on the membrane and induce apoptotic BAK pores and cytochrome c release. Thus, the results suggest that Aβ oligomers function as apoptotic ligands and hijack the intrinsic apoptotic pathway to cause unintended neuronal cell death.
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: Jaewook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: Yoosoo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Kookmin University, Seoul, Republic of Korea.
authors.forename: Seung Soo
authors.initials: SS
authors.lastname: Song
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea; Department of Chemistry, Kookmin University, Seoul, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Na
authors.affiliation: Department of Biochemistry and Molecular Biology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
authors.forename: Kyoung Joon
authors.initials: KJ
authors.lastname: Oh
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: Cherlhyun
authors.initials: C
authors.lastname: Jeong
authors.affiliation: Department of Chemistry, Kookmin University, Seoul, Republic of Korea.
authors.forename: Yeon Gyu
authors.initials: YG
authors.lastname: Yu
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea; Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, Iowa. Electronic address: colishin@iastate.edu.
authors.forename: Yeon-Kyun
authors.initials: YK
authors.lastname: Shin
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016062:Porosity; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D016875:tau Proteins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D051023:BH3 Interacting Domain Death Agonist Protein; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D050998:bcl-2 Homologous Antagonist-Killer Protein; D016875:tau Proteins; D045304:Cytochromes c