Background: While traditional models of Alzheimer's disease focused on large fibrillar deposits of the Abeta42 amyloid peptide in the brain, recent work suggests that the major pathogenic effects may be attributed to SDS-stable oligomers of Abeta42. These Abeta42 oligomers represent a rational target for therapeutic intervention, yet factors governing their assembly are poorly understood.
Results: We describe a new yeast model system focused on the initial stages of Abeta42 oligomerization. We show that the activity of a fusion of Abeta42 to a reporter protein is compromised in yeast by the formation of SDS-stable low-n oligomers. These oligomers are reminiscent of the low-n oligomers formed by the Abeta42 peptide in vitro, in mammalian cell culture, and in the human brain. Point mutations previously shown to inhibit Abeta42 aggregation in vitro, were made in the Abeta42 portion of the fusion protein. These mutations both inhibited oligomerization and restored activity to the fusion protein. Using this model system, we found that oligomerization of the fusion protein is stimulated by millimolar concentrations of the yeast prion curing agent guanidine. Surprisingly, deletion of the chaperone Hsp104 (a known target for guanidine) inhibited oligomerization of the fusion protein. Furthermore, we demonstrate that Hsp104 interacts with the Abeta42-fusion protein and appears to protect it from disaggregation and degradation.
Conclusion: Previous models of Alzheimer's disease focused on unravelling compounds that inhibit fibrillization of Abeta42, i.e. the last step of Abeta42 assembly. However, inhibition of fibrillization may lead to the accumulation of toxic oligomers of Abeta42. The model described here can be used to search for and test proteinacious or chemical compounds for their ability to interfere with the initial steps of Abeta42 oligomerization. Our findings suggest that yeast contain guanidine-sensitive factor(s) that reduce the amount of low-n oligomers of Abeta42. As many yeast proteins have human homologs, identification of these factors may help to uncover homologous proteins that affect Abeta42 oligomerization in mammals.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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