ABSTRACT
Alzheimer's disease (AD), an age-related neurodegenerative disorder, is the most common form of dementia, and the seventh-leading cause of death in the United States. Current treatments offer only symptomatic relief; thus, there is a great need for new treatments with disease-modifying potential. One pathological hallmark of AD is so-called senile plaques, mainly made up of ß-sheet-rich assemblies of 40- or 42-residue amyloid ß-peptides (Aß). Hence, inhibition of Aß aggregation is actively explored as an option to prevent or treat AD. Congo red (CR) has been widely used as a model antiamyloid agent to prevent Aß aggregation. Herein, we report detailed morphological studies on the effect of CR as an antiamyloid agent, by circular dichroism spectroscopy, photo-induced cross-linking reactions, and atomic force microscopy. We also demonstrate the effect of CR on a preaggregated sample of Aß(1-40). Our result suggests that Aß(1-40) follows a different path for aggregation in the presence of CR.
Subject(s)
Amyloid beta-Peptides/drug effects , Amyloid/drug effects , Congo Red/pharmacology , Peptide Fragments/drug effects , Amyloid/ultrastructure , Amyloid beta-Peptides/chemistry , Circular Dichroism , Cross-Linking Reagents/pharmacology , Electrophoresis, Polyacrylamide Gel , Humans , Microscopy, Atomic Force , Peptide Fragments/chemistry , Photochemistry , Protein Structure, Secondary/drug effectsABSTRACT
Alzheimer's disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid beta-peptides (Abeta) into neurotoxic oligo-/polymeric beta-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in Abeta aggregation, but most Abeta aggregation inhibitors have targeted the central region around residues 16-23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32-37 of Abeta, to target its C-terminal region. We measured the peptides' abilities to retard beta-sheet and fibril formation of Abeta and to reduce Abeta neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human Abeta(1-42).