Toxicity mediated by soluble oligomers of beta-amyloid(1-42) on cholinergic SN56.B5.G4 cells.
Alzheimer's disease (AD) is characterized by cholinergic dysfunction and progressive basal forebrain cell loss which has been assumed to be as a result of the extensive accumulation of beta-amyloid (Abeta). In addition to Abeta fibrillar assemblies, there are pre-fibrillar forms that have been shown to be neurotoxic, although their role in cholinergic degeneration is still not known. Using the cholinergic cell line SN56.B5.G4, we investigated the effect of different Abeta(1-42) aggregates on cell viability. In our model, only soluble oligomeric but not fibrillar Abeta(1-42) forms induced toxicity in cholinergic cells. To determine whether the neurotoxicity of oligomeric Abeta(1-42) was caused by its oxidative potential, we performed microarray analysis of SN56.B5.G4 cells treated either with oligomeric Abeta(1-42) or H(2)O(2). We showed that genes affected by Abeta(1-42) differed from those affected by non-specific oxidative stress. Many of the genes affected by Abeta(1-42) were present in the endoplasmic reticulum (ER), Golgi apparatus and/or otherwise involved in protein modification and degradation (chaperones, ATF6), indicating a possible role for ER-mediated stress in Abeta-mediated toxicity. Moreover, a number of genes, which are known to be involved in AD (clusterin, Slc18a3), were identified. This study provides important leads for the understanding of oligomeric Abeta(1-42) toxicity in cholinergic cells, which may account in part for cholinergic degeneration in AD.
Heinitz
Katrin
K
Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany.
Beck
Martin
M
Schliebs
Reinhard
R
Perez-Polo
J Regino
JR
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000506:poisoning*; D000818:Animals; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000506:poisoning*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D016877:Oxidants; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006861:Hydrogen Peroxide; D002795:Choline O-Acetyltransferase