Journal article
Mechanistic Investigation of the Inhibition of Aβ42 Assembly and Neurotoxicity by Aβ42 C-terminal Fragments
Biochemistry (Easton), v 49(30), pp 6358-6364
03 Aug 2010
PMID: 20568734
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Oligomeric forms of amyloid β-protein (Aβ) are key neurotoxins in Alzheimer's disease (AD). Previously, we found that C-terminal fragments (CTFs) of Aβ42 interfered with assembly of full-length Aβ42 and inhibited Aβ42-induced toxicity. To decipher the mechanism(s) by which CTFs affect Aβ42 assembly and neurotoxicity, here, we investigated the interaction between Aβ42 and CTFs using photo-induced cross-linking and dynamic light scattering. The results demonstrate that distinct parameters control CTF inhibition of Aβ42 assembly and Aβ42-induced toxicity. Inhibition of Aβ42-induced toxicity was found to correlate with stabilization of oligomers with hydrodynamic radius (
R
H
) = 8–12 nm and attenuation of formation of oligomers with
R
H
= 20–60 nm. In contrast, inhibition of Aβ42 paranucleus formation correlated with CTF solubility and the degree to which CTFs formed amyloid fibrils themselves but did not correlate with inhibition of Aβ42-induced toxicity. Our findings provide an important insight into the mechanisms by which different CTFs inhibit the toxic effect of Aβ42 and suggest that stabilization of non-toxic Aβ42 oligomers is a promising strategy for designing inhibitors of Aβ42 neurotoxicity.
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Details
- Title
- Mechanistic Investigation of the Inhibition of Aβ42 Assembly and Neurotoxicity by Aβ42 C-terminal Fragments
- Creators
- Huiyuan Li - Department of Neurology, David Geffen School of MedicineBernhard H Monien - Department of Neurology, David Geffen School of MedicineAleksey Lomakin - Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MAReeve Zemel - Department of Neurology, David Geffen School of MedicineErica A Fradinger - Department of Neurology, David Geffen School of MedicineMiao Tan - Department of Psychiatry and Biobehavioral Sciences, David Geffen School of MedicineSean M Spring - Department of Neurology, David Geffen School of MedicineBrigita Urbanc - Physics Department, Drexel University, Philadelphia, PACui-Wei Xie - Department of Psychiatry and Biobehavioral Sciences, David Geffen School of MedicineGeorge B Benedek - Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MAGal Bitan - Department of Neurology, David Geffen School of Medicine
- Publication Details
- Biochemistry (Easton), v 49(30), pp 6358-6364
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000280416100008
- Scopus ID
- 2-s2.0-77955032523
- Other Identifier
- 991014878349004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology