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Differential modification of Cys10 alters transthyretin's effect on beta-amyloid aggregation and toxicity
- Source :
- Protein engineering, designselection : PEDS. 22(8)
- Publication Year :
- 2009
-
Abstract
- Tg2576 mice produce high levels of beta-amyloid (Abeta) and develop amyloid deposits, but lack neurofibrillary tangles and do not suffer the extensive neuronal cell loss characteristic of Alzheimer's disease. Protection from Abeta toxicity has been attributed to up-regulation of transthyretin (TTR), a normal component of plasma and cerebrospinal fluid. We compared the effect of TTR purified from human plasma (pTTR) with that produced recombinantly (rTTR) on Abeta aggregation and toxicity. pTTR slowed Abeta aggregation but failed to protect primary cortical neurons from Abeta toxicity. In contrast, rTTR accelerated aggregation, while effectively protecting neurons. This inverse correlation between Abeta aggregation kinetics and toxicity is consistent with the hypothesis that soluble intermediates rather than insoluble fibrils are the most toxic Abeta species. We carried out a detailed comparison of pTTR with rTTR to ascertain the probable cause of these different effects. No differences in secondary, tertiary or quaternary structure were detected. However, pTTR differed from rTTR in the extent and nature of modification at Cys10. We hypothesize that differential modification at Cys10 regulates TTR's effect on Abeta aggregation and toxicity.
- Subjects :
- Amyloid
Cell Survival
Bioengineering
Fibril
Biochemistry
Mass Spectrometry
Mice
Microscopy, Electron, Transmission
Animals
Prealbumin
Cysteine
Beta (finance)
Molecular Biology
Polyacrylamide gel electrophoresis
Cells, Cultured
Neurons
Amyloid beta-Peptides
biology
Chemistry
Circular Dichroism
Hydrogen-Ion Concentration
Original articles
Recombinant Proteins
Transthyretin
Kinetics
Toxicity
biology.protein
Protein quaternary structure
Electrophoresis, Polyacrylamide Gel
Female
Protein Multimerization
Biotechnology
Subjects
Details
- ISSN :
- 17410134
- Volume :
- 22
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Protein engineering, designselection : PEDS
- Accession number :
- edsair.doi.dedup.....f381fbcc4ce303ee100ae9e8e4e1438c