Only amyloidogenic intermediates of transthyretin induce apoptosis.
In diseases like Alzheimer's disease and familial amyloidotic polyneuropathy (FAP) amyloid deposits co-localize with areas of neurodegeneration. FAP is associated with mutations of the plasma protein transthyretin (TTR). We can here show an apoptotic effect of amyloidogenic mutants of TTR on a human neuroblastoma cell line. Toxicity could be blocked by catalase indicating a free oxygen radical dependent mechanism. The toxic effect was dependent on the state of aggregation and unexpectedly mature fibrils from FAP-patients who failed to exert an apoptotic response. Morphological studies revealed a correlation between toxicity and the presence of immature amyloid. Thus, we can show that toxicity is associated with early stages of fibril formation and propose that mature full-length fibrils represent an inert end stage, which might serve as a rescue mechanism.
Andersson
Karin
K
Department of Cell and Molecular Biology, Umeå University, S-901 87 Umeå, Sweden.
Olofsson
Anders
A
Nielsen
Ellen Holm
EH
Svehag
Sven-Erik
SE
Lundgren
Erik
E
D000544:Alzheimer Disease / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020287:In Situ Nick-End Labeling; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D011228:Prealbumin / Q000235:genetics / Q000633:toxicity* / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011228:Prealbumin; C078592:amyloid beta-protein (1-40); D002374:Catalase