C-terminal peptides coassemble into Abeta42 oligomers and protect neurons against Abeta42-induced neurotoxicity.
Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of Abeta42 are believed to be the main cause of AD; therefore, disruption of Abeta oligomerization is a promising approach for developing therapeutics for AD. Formation of Abeta42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of Abeta42 may get incorporated into oligomers of Abeta42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using Abeta fragments with the general formula Abeta(x-42) (x = 28-39). A cell viability screen identified Abeta(31-42) as the most potent inhibitor. In addition, the shortest peptide, Abeta(39-42), also had high activity. Both Abeta(31-42) and Abeta(39-42) inhibited Abeta-induced cell death and rescued disruption of synaptic activity by Abeta42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of Abeta42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with Abeta42 to form heterooligomers. Thus, Abeta(31-42) and Abeta(39-42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure-activity approach.
Fradinger
Erica A
EA
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Monien
Bernhard H
BH
Urbanc
Brigita
B
Lomakin
Aleksey
A
Tan
Miao
M
Li
Huiyuan
H
Spring
Sean M
SM
Condron
Margaret M
MM
Cruz
Luis
L
Xie
Cui-Wei
CW
Benedek
George B
GB
Bitan
Gal
G
D000544:Alzheimer Disease / Q000378:metabolism* / Q000517:prevention & control*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D003198:Computer Simulation; D004594:Electrophysiology; D006624:Hippocampus / Q000502:physiology; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051381:Rats; D012995:Solubility
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C570535:amyloid beta-peptide (39-42); C075222:amyloid beta-protein (1-42)
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