Aβ1-42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner

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 beta-amyloid (A beta). In this study, we used preparations enriched in oligomeric or fibrillar A beta(1-42) to investigate the role of the conformational state of A beta in UPR activation in differentiated neuroblastoma cells. Both oligomeric and fibrillar A beta(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 A beta(1-42). We showed that oligomeric A beta(1-42) is significantly more toxic to cells primed for UPR than is fibrillar A beta(1-42), indicating that activation of the UPR contributes to oligomer-specific A beta(1-42) toxicity. Because UPR activation is observed in AD brain at a stage that precedes the massive fibrillar A beta deposition and tangle formation, this may indicate a role for nonfibrillar A beta in the induction of the UPR in AD neurons.