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Reversal of temperature-induced conformational changes in the amyloid-beta peptide, Abeta40, by the beta-sheet breaker peptides 16-23 and 17-24.
- Source :
- British Journal of Pharmacology; Oct2009, Vol. 158 Issue 4, p1165-1172, 8p
- Publication Year :
- 2009
-
Abstract
- <bold>Background and Purpose: </bold>Aggregates of the protein amyloid-beta (Abeta) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Abeta, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value.<bold>Experimental Approach: </bold>We investigated ex vivo the temperature-sensitive regions of Abeta1-40 (Abeta40) and their interactions with octapeptides derived from sequences within Abeta40 -beta-sheet breaker peptides (betaSBP) - using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5-10, 9-14 and 17-21 within Abeta40.<bold>Key Results: </bold>Temperature-dependent conformational changes were observed in Abeta40 at epitopes 9-14 and 17-21 at 36-38 and 36-40 degrees C respectively. The betaSBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, betaSBPs 16-23 and 17-24 increased digestion of Abeta40 by protease K, indicating a decreased aggregation of Abeta40, whereas betaSBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that beta-sheet formation in Abeta40 at 38 degrees C was reduced with betaSBPs 16-23 and 17-24.<bold>Conclusions and Implications: </bold>The epitopes 9-14 and 17-21 are the temperature-sensitive regions within Abeta40. The betaSBPs, Abeta16-23 and 17-24 reversed temperature-induced beta-sheet formation, and decreased Abeta40 aggregation. The results suggest that the 17-23 epitope of Abeta40 is crucially involved in preventing Abeta40 aggregation and consequent deposition of Abeta40 in AD brain. [ABSTRACT FROM AUTHOR]
- Subjects :
- AMYLOID
AMYLOID beta-protein
PEPTIDES
ALZHEIMER'S disease
CARCINOGENESIS
TARGETED drug delivery
TEMPERATURE
BIOLOGICAL assay
NUCLEOTIDE sequence
PROTEINS
RESEARCH
HYDROGEN-ion concentration
TIME
RESEARCH methodology
PROTEOLYTIC enzymes
MEDICAL cooperation
EVALUATION research
DOCUMENTATION
COMPARATIVE studies
MOLECULAR structure
AMINO acids
SPECTRUM analysis
ANTIGENS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 158
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 65012744
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00384.x