The interaction of amyloid β-peptide (Aβ) with cell membranes is believed to play a central role in the pathogenesis of Alzheimer's disease. In particular, recent experimental evidence indicates that bilayer and monolayer membranes accelerate the aggregation and amyloid fibril formation rate of Aβ. Understanding that interaction could help develop therapeutic strategies for treatment of the disease. Trehalose, a disaccharide of glucose, has been shown to be effective in preventing the aggregation of numerous proteins. It has also been shown to delay the onset of certain amyloid-related diseases in a mouse model. Using Langmuir monolayers and molecular simulations of the corresponding system, we study several thermodynamic and kinetic aspects of the insertion of Aβ peptide into DPPG monolayers in water and trehalose subphases. In the water subphase, the insertion of the Aβ peptide into the monolayer exhibits a lag time which decreases with increasing temperature of the subphase. In the presence of trehalose, the lag time is completely eliminated and peptide insertion is completed within a shorter time period compared to that observed in pure water. Molecular simulations show that more peptide is inserted into the monolayer in the water subphase, and that such insertion is deeper. The peptide at the monolayer interface orients itself parallel to the monolayer, while it inserts with an angle of 50° in the trehalose subphase. Simulations also show that trehalose reduces the conformational change that the peptide undergoes when it inserts into the monolayer. This observation helps explain the experimentally observed elimination of the lag time by trehalose and the temperature dependence of the lag time in the water subphase.
Bibliographical noteFunding Information:
J.J.d.P. and N.L.A. thank the NSF for support of this work through the University of Wisconsin Materials Research Science and Engineering Center on Nanostructured Interfaces. J.J.d.P. is also grateful to NSF for support through grant CBET-0755730.
- Alzheimer's disease
- Amyloid beta peptide