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Molecular chirality mediated amyloid formation on phospholipid surfaces
Xue Wang1,2, Cunli Wang2, Huiying Chu3
1State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology 122 Luoshi Road Wuhan 430070 P. R. China.
Chemical Science
|June 14, 2021
Summary
Chiral phospholipid bilayers incorporating d-amino acids significantly inhibit amyloid-β aggregation and related cytotoxicity, offering a potential strategy for Alzheimer
Area of Science:
- Biochemistry
- Neuroscience
- Materials Science
Background:
- Alzheimer's disease (AD) involves amyloid-β (Aβ) misfolding and aggregation on biological membranes.
- The influence of molecular chirality on Aβ aggregation at membrane interfaces is poorly understood.
Purpose of the Study:
- To investigate the effect of chiral phospholipid surfaces on Aβ(1-40) aggregation and cytotoxicity.
- To explore the potential of d-amino acid-modified liposomes for AD prevention.
Main Methods:
- Synthesis of l- and d-aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (l-/d-Asp-DPPE) liposomes.
- Assessing Aβ(1-40) nucleation and elongation inhibition.
- Evaluating Aβ(1-40)-induced cytotoxicity rescue and cell viability.
- Employing mechanism analysis and molecular dynamics simulations.
Main Results:
- l-Asp-DPPE liposomes showed minor inhibition of Aβ(1-40) nucleation, with no effect on elongation.
- d-Asp-DPPE liposomes strongly inhibited both Aβ(1-40) nucleation and elongation.
- Both liposome types demonstrated biocompatibility and rescued Aβ(1-40)-aggregation induced cytotoxicity.
- d-Asp-DPPE liposomes provided higher cell viability, indicating significant chiral discrimination.
- Differential electrostatic interactions between Aβ(1-40) Lys16 and Asp moieties were identified as the mechanism.
Conclusions:
- Chirality at the phospholipid interface critically influences Aβ(1-40) aggregation kinetics and cytotoxicity.
- d-Asp-DPPE liposomes exhibit potent anti-amyloidogenic and neuroprotective effects.
- Incorporating d-amino acids into liposomes presents a promising avenue for Alzheimer's disease prevention strategies.
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