Abeta 1-42 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 (Abeta). In this study, we used preparations enriched in oligomeric or fibrillar Abeta (1-42) to investigate the role of the conformational state of Abeta in UPR activation in differentiated neuroblastoma cells. Both oligomeric and fibrillar Abeta (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 Abeta (1-42). We showed that oligomeric Abeta (1-42) is significantly more toxic to cells primed for UPR than is fibrillar Abeta (1-42), indicating that activation of the UPR contributes to oligomer-specific Abeta (1-42) toxicity. Because UPR activation is observed in AD brain at a stage that precedes the massive fibrillar Abeta deposition and tangle formation, this may indicate a role for nonfibrillar Abeta in the induction of the UPR in AD neurons.
Chafekar
Sidhartha M
SM
Neurogenetics Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
Hoozemans
Jeroen J M
JJ
Zwart
Rob
R
Baas
Frank
F
Scheper
Wiep
W
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity / Q000648:ultrastructure; D052160:Benzothiazoles; D037281:Calnexin / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005456:Fluorescent Dyes / Q000378:metabolism; D005562:Formazans / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity / Q000648:ultrastructure; D011487:Protein Conformation / Q000187:drug effects*; D013312:Stress, Physiological / Q000139:chemically induced*; D013696:Temperature; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D005562:Formazans; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D014415:Tunicamycin; D037281:Calnexin; C079782:MTT formazan; C009462:thioflavin T; D004121:Dimethyl Sulfoxide