Effect of trehalose on the interaction of Alzheimer's Aβ-peptide and anionic lipid monolayers

Abstract

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.

2DIR Spectroscopy of Human Amylin Fibrils Reflects Stable β-Sheet Structure

“…This force field has been used extensively for protein simulations, 71,72 and was shown to provide good agreement with experiment in our recent studies of IAPP monomers 73,74 and peptide aggregation. 75,76 The ionization states of the amino acid side chains were assigned on the basis of their intrinsic pKa values. Our model of the amyloid protofilament has five stacked pairs of hIAPP, as in Figure 2(a), and has a net positive charge of +30 (+3 on each peptide).…”

Targeting Assembly and Disassembly of Protein Aggregates

“…Trehalose stabilizes an a-helix conformation of Ab peptides, and reduces the lag time needed for their deep insertion into the membrane. Membrane-inserted Ab species are more disordered/less toxic than their counterparts in trehalose-free medium, and may contribute to an overall neuroprotective effect (lower membrane disruption in Ab peptide-challenged neuronal cells treated with mM trehalose) [280]. The direct interaction between trehalose and polyQ proteins [281], prion proteins [282], and a-synuclein [283] is reported in the literature, to substantiate a mixed autophagy inducer/anti-aggregation profile for trehalose in NDDs.…”

“…It forms a hydrophilic layer around Ab 40 monomers that weakens intermonomeric, aggregation-prone hydrophobic interactions [279]. Trehalose interacts with the head groups of phospholipids in lipid membranes, and its presence (100 mM) causes the rapid insertion of Ab monomers in the membrane [280]. Trehalose stabilizes an a-helix conformation of Ab peptides, and reduces the lag time needed for their deep insertion into the membrane.…”

Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology

“…The ability of trehalose to stabilize aggregation-prone protein molecules is under investigation as a possible approach in the treatment of polyglutamine diseases, such as Huntington’s chorea12,13 and Alzheimer’s disease 14,15…”