Journal article
Biophysical Characterization of Aβ42 C-terminal Fragments—Inhibitors of Aβ42 Neurotoxicity
Biochemistry (Easton), v 49(6), pp 1259-1267
16 Feb 2010
PMID: 20050679
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A key event in Alzheimer’s disease (AD) is age-dependent, brain accumulation of amyloid β-protein (Aβ) leading to Aβ self-association into neurotoxic oligomers. Previously, we showed that Aβ oligomerization and neurotoxicity could be inhibited by C-terminal fragments (CTFs) of Aβ42. Because these CTFs are highly hydrophobic, we asked if they themselves aggregated and if so, what parameters regulated their aggregation. To answer these questions, we investigated the dependence of CTF aqueous solubility, aggregation kinetics and morphology on peptide length and sequence, and the correlation between these characteristics and inhibition of Aβ42-induced toxicity. We found that CTFs up to 8-residues long were soluble at concentrations >100 µM and had a low propensity to aggregate. Longer CTFs were soluble at ~1–80 µM and most, but not all, readily formed β-sheet-rich fibrils. Comparison to Aβ40-derived CTFs showed that the C-terminal dipeptide I41-A42 strongly promoted aggregation. Aggregation propensity correlated with previously reported tendency to form β-hairpin conformation but not with inhibition of Aβ42-induced neurotoxicity. The data enhance our understanding of the physical characteristics that affect CTF activity and advance our ability to design, synthesize, and test future generations of inhibitors.
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Details
- Title
- Biophysical Characterization of Aβ42 C-terminal Fragments—Inhibitors of Aβ42 Neurotoxicity
- Creators
- Huiyuan Li - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, CA, 90095Bernhard H Monien - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, CA, 90095Erica A Fradinger - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, CA, 90095Brigita Urbanc - Physics Department, Drexel University, 3141 Chestnut St. Philadelphia, PA 19104Gal Bitan - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, CA, 90095
- Publication Details
- Biochemistry (Easton), v 49(6), pp 1259-1267
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000274342000023
- Scopus ID
- 2-s2.0-76749102996
- Other Identifier
- 991014877980004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology