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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
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Exploring the relation between the oligomeric structure and membrane damage by a study on rat islet amyloid
Tong Lu1, Feihong Meng1, Ying Wei1
1State Key Laboratory of Supramolecular Structure and Materials, Jilin University, 2699 Qianjin Avenue, Changchun 130012, P. R. China. feili@jlu.edu.cn.
Physical Chemistry Chemical Physics : PCCP
|March 21, 2018
Summary
Smaller rat islet amyloid polypeptide (rIAPP) oligomers (<50 nm) are more cytotoxic, damaging cell membranes. Larger assemblies reduce this disruptive potency, revealing a size-dependent mechanism for amyloid-induced membrane damage.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Amyloid peptide fibrillation intermediates are crucial for both fibrillation and cytotoxicity.
- Prefibrillar intermediates are heterogeneous and transient, posing challenges for characterization.
- Rat islet amyloid polypeptide (rIAPP) exhibits weak fibrillation but is cytotoxic.
Purpose of the Study:
- To characterize prefibrillar species of rIAPP at various oligomeric states.
- To investigate the mechanism of membrane damage induced by rIAPP oligomers.
- To explore the relationship between oligomer size, structure, and membrane disruptive efficiency.
Main Methods:
- Preparation of rIAPP oligomers under diverse conditions.
- Structural and morphological characterization using CD, TEM, and DLS.
- Membrane interaction and disruption assessment via NMR spectroscopy and leaking assays with POPC/POPG membranes.
Main Results:
- Oligomers below ~50 nm in diameter showed increased membrane-damaging potential.
- Assemblies larger than ~50 nm exhibited significantly reduced disruptive potency.
- Smaller, more damaging oligomers displayed enhanced alpha-helix stability at the membrane and stronger binding.
Conclusions:
- The interplay between oligomeric size and hydrophobic exposure dictates rIAPP's membrane damage mechanism.
- A size limit exists, beyond which increased oligomer size diminishes membrane disruptive potency.
- Hydrophobic exposure correlates with disruptive potency only for oligomers below a specific size threshold.
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