All-D-enantiomers of beta-amyloid exhibit similar biological properties to all-L-beta-amyloids.
The amyloidogenic peptide beta-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of Abeta neurotoxicity, we synthesized the all-D- and all-L-stereoisomers of the neurotoxic truncated form of Abeta (Abeta25-35) and the full-length peptide (Abeta1-42) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of Abeta result not from stereoisomer-specific ligand-receptor interactions but rather from Abeta cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these beta-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.
Cribbs
D H
DH
Institute for Brain Aging and Dementia, Departments of Psychobiology, University of California Irvine, Irvine, California 92697-4540, USA. dhcribbs@uci.edu
Pike
C J
CJ
Weinstein
S L
SL
Velazquez
P
P
Cotman
C W
CW
D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006624:Hippocampus / Q000187:drug effects*; D007536:Isomerism; D009474:Neurons / Q000187:drug effects*; D051381:Rats
D016229:Amyloid beta-Peptides