TAILIEUCHUNG - Báo cáo khoa học: Co-incorporation of Ab40 and Ab42 to form mixed pre-fibrillar aggregates

Senile plaques, the invariable hallmark and likely proximal cause of Alzheimer’s disease (AD), are structured deposi-tions of the 40- and 42-residue forms of the Abpeptide. Conversely, diffuse plaques, which are not associated with neurodegeneration, consist mainly of unstructured Ab42. We have investigated the interaction between Ab40 and Ab42 through an assay, which involves labeling both vari-ants with an environment-sensitive fluorophore. | Eur. J. Biochem. 270 654-663 2003 FEBS 2003 doi Co-incorporation of Ap40 and Ap42 to form mixed pre-fibrillar aggregates David Frost1 Paul M. Gorman1 Christopher M. Yip2 and Avijit Chakrabartty1 1 Division of Molecular and Structural Biology Ontario Cancer Institute and Department of Medical Biophysics and department of Chemical Engineering and Applied Chemistry Institute of Biomaterials and Biomedical Engineering Department of Biochemistry University of Toronto Toronto Ontario Canada Senile plaques the invariable hallmark and likely proximal cause of Alzheimer s disease AD are structured depositions of the 40- and 42-residue forms of the Ab peptide. Conversely diffuse plaques which are not associated with neurodegeneration consist mainly of unstructured Ab42. We have investigated the interaction between Ap40 and Ap42 through an assay which involves labeling both variants with an environment-sensitive fluorophore. We have monitored association of Ab without fibrillar seeds which allows investigation of molecular species preceding fibrils. Immediately upon mixture Ab40 and Ab42 associate into mixed aggregates in which the peptides are unstructured and relatively accessible to water. When left to incubate for an extended period larger more tightly packed aggregates which show secondary structure replace the small unstructured aggregates formed earlier. Our results show that in vitro the two Ab variants coassemble early in the fibrillogenesis pathway. The ease of formation for mixed and homogeneous aggregates is similar. A change in the local Ab variant ratio can therefore have a significant impact on Ab aggregation indeed such a change has been reported in some types of familial AD. Keywords Alzheimer s disease amyloid fibril peptide fluorescence. Alzheimer s disease AD is a significant and increasing health concern. Neurohistological studies have uncovered several hallmarks that distinguish the AD brain from its normal counterpart. .

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