A β 1-42 Induces Mild Endoplasmic Reticulum Stress in an Aggregation State–Dependent Manner

Abstract

Alzheimer's disease (AD) is characterized by the aggregation of misfolded proteins. Previously we reported activation of the unfolded protein response (UPR) in AD neurons. A potential source for UPR activation in AD neurons may be the increased levels of β-amyloid (Aβ). In this study, we used preparations enriched in oligomeric or fibrillar Aβ _1-42 to investigate the role of the conformational state of Aβ in UPR activation in differentiated neuroblastoma cells. Both oligomeric and fibrillar Aβ _1-42 do not induce BiP expression to the extent that it can be detected in a pool of cells. However, using a fluorescent UPR reporter cell line that allows analysis of individual cells, we demonstrated mild activation of the UPR by oligomeric but not fibrillar Aβ _1-42. We showed that oligomeric Aβ _1-42 is significantly more toxic to cells primed for UPR than is fibrillar Aβ _1-42, indicating that activation of the UPR contributes to oligomer-specific Aβ _1-42 toxicity. Because UPR activation is observed in AD brain at a stage that precedes the massive fibrillar Aβ deposition and tangle formation, this may indicate a role for nonfibrillar Aβ in the induction of the UPR in AD neurons.