title: alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells.
abstract: alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part of Alzheimer's dementia related plaques. However, the role of alpha-synuclein in pathomechanism of Alzheimer's disease remains elusive. In particular, the relationship between alpha-synuclein and amyloid beta is unknown. In the present study we showed the involvement of alpha-synuclein in amyloid beta secretion and in the mechanism of amyloid beta evoked mitochondria dysfunction and cell death. Rat pheochromocytoma PC12 cells transfected with amyloid beta precursor protein bearing Swedish double mutation (APPsw) and control PC12 cells transfected with empty vector were used in this study. alpha-Synuclein (10microM) was found to increase by twofold amyloid beta secretion from control and APPsw PC12 cells. Moreover, alpha-synuclein decreased the viability of PC12 cells by about 50% and potentiated amyloid beta toxicity leading to mitochondrial dysfunction and caspase-dependent programmed cell death. Inhibitor of caspase-3 (Z-DEVD-FMK, 100microM), and a mitochondrial permeability transition pore blocker, cyclosporine A (2microM) protected PC12 cells against alpha-synuclein or amyloid beta evoked cell death. In contrast Z-DEVD-FMK and cyclosporine A were ineffective in APPsw cells containing elevated amount of amyloid beta treated with alpha-synuclein. It was found that the inhibition of neuronal and inducible nitric oxide synthase reversed the toxic effect of alpha-synuclein in control but not in APPsw cells. Our results indicate that alpha-synuclein enhances the release and toxicity of amyloid beta leading to nitric oxide mediated irreversible mitochondria dysfunction and caspase-dependent programmed cell death.
authors.affiliation: Medical Research Center, Polish Academy of Sciences, Department of Cellular Signaling, Pawińskiego 5 str., 02-106 Warsaw, Poland. aniakazmierczak@gmail.com
authors.forename: Anna
authors.initials: A
authors.lastname: Kazmierczak
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Strosznajder
authors.forename: Agata
authors.initials: A
authors.lastname: Adamczyk
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000819:agonists / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D012634:Bodily Secretions / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I