Journal article
C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity
Proceedings of the National Academy of Sciences - PNAS, v 105(37), pp 14175-14180
16 Sep 2008
PMID: 18779585
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of Aβ42 are believed to be the main cause of AD; therefore, disruption of Aβ oligomerization is a promising approach for developing therapeutics for AD. Formation of Aβ42 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 Aβ42 may get incorporated into oligomers of Aβ42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using Aβ fragments with the general formula Aβ(
x
−42) (
x
= 28–39). A cell viability screen identified Aβ(31–42) as the most potent inhibitor. In addition, the shortest peptide, Aβ(39–42), also had high activity. Both Aβ(31–42) and Aβ(39–42) inhibited Aβ-induced cell death and rescued disruption of synaptic activity by Aβ42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of Aβ42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with Aβ42 to form heterooligomers. Thus, Aβ(31–42) and Aβ(39–42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure–activity approach.
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Details
- Title
- C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity
- Creators
- Erica A Fradinger - Departments of Neurology andBernhard H Monien - Departments of Neurology andBrigita Urbanc - Center for Polymer Studies, Department of Physics, Boston University, Boston, MA 02215; andAleksey Lomakin - Center for Material Science and Engineering, Material Processing CenterMiao Tan - Psychiatry and Biobehavioral Sciences, David Geffen School of MedicineHuiyuan Li - Departments of Neurology andSean M Spring - Departments of Neurology andMargaret M Condron - Departments of Neurology andLuis Cruz - Center for Polymer Studies, Department of Physics, Boston University, Boston, MA 02215; andCui-Wei Xie - Psychiatry and Biobehavioral Sciences, David Geffen School of MedicineGeorge B Benedek - Center for Material Science and Engineering, Material Processing CenterGal Bitan - Departments of Neurology and
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 105(37), pp 14175-14180
- Publisher
- National Academy of Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000259438500088
- Scopus ID
- 2-s2.0-52949100595
- Other Identifier
- 991014877917504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology