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 (A beta). In addition to A beta 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 A beta(1-42) aggregates on cell viability. In our model, only soluble oligomeric but not fibrillar A beta(1-42) forms induced toxicity in cholinergic cells. To determine whether the neurotoxicity of oligomeric A beta(1-42) was caused by its oxidative potential, we performed microarray analysis of SN56.B5.G4 cells treated either with oligomeric A beta(1-42) or H2O2. We showed that genes affected by A beta(1-42) differed from those affected by non-specific oxidative stress. Many of the genes affected by A beta(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 A beta-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 A beta(1-42) toxicity in cholinergic cells, which may account in part for cholinergic degeneration in AD.