Controlling amyloid-beta peptide(1-42) oligomerization and toxicity by fluorinated nanoparticles.

The amyloid-beta peptide (Abeta) is a major fibrillar component of neuritic plaques in Alzheimer's disease brains and is related to the pathogenesis of the disease. Soluble oligomers that precede fibril formation have been proposed as the main neurotoxic species that contributes to neurodegeneration and dementia. We hypothesize that oligomerization and cytotoxicity can be repressed by nanoparticles (NPs) that induce conformational changes in Abeta42. We show here that fluorinated and hydrogenated NPs with different abilities to change Abeta42 conformation influence oligomerization as assessed by atomic force microscopy, immunoblot and SDS-PAGE. Fluorinated NPs, which promote an increase in alpha-helical content, exert an antioligomeric effect, whereas hydrogenated analogues do not and lead to aggregation. Cytotoxicity assays confirmed our hypothesis by indicating that the conformational conversion of Abeta42 into an alpha-helical-enriched secondary structure also has antiapoptotic activity, thereby increasing the viability of cells treated with oligomeric species.

Is the viscoelasticity of Alzheimer's Abeta42 peptide oligomers a general property of protein oligomers related to their toxicity?

The largest group of protein misfolding diseases is associated with the conversion of specific peptides or proteins from their soluble functional states into highly organized fibrillar aggregates named amyloid fibrils or plaques. The amyloid-beta peptide (Abeta) is involved in pathogenesis of Alzheimer's disease (AD), being the main constituent of the amyloid plaques found in AD brains. Abeta is a proteolytic product of a transmembrane protein and due to its amphipathicity it may be retained in the membrane, and this has been shown to be crucial for neurotoxicity. Hydrophobic and electrostatic interactions strongly influence its conformation and aggregation both in solution and at interfaces. Appropriate solid sorbent surfaces were used to study the different interactions independently. Quartz crystal microbalance with dissipation monitoring (QCM-D), atomic force microscopy (AFM) and attenuated total reflection infrared spectroscopy (ATR-IR) were employed for the investigation of the behavior of Abeta peptides on planar surfaces. Abeta peptides have high affinity for hydrophobic and rough surfaces that promote aggregation. QCM-D measurements indicate that the oligomers are soft when compared to monomers, and this property might be related to the bioactivity of protein oligomers in general.

Randomization of amyloid-ß-peptide(1-42) conformation by sulfonated and sulfated nanoparticles reduces aggregation and cytotoxicity.

The amyloid-ß peptide (Aß) plays a central role in the mechanism of Alzheimer's disease, being the main constituent of the plaque deposits found in AD brains. Aß amyloid formation and deposition are due to a conformational switching to a ß-enriched secondary structure. Our strategy to inhibit Aß aggregation involves the re-conversion of Aß conformation by adsorption to nanoparticles. NPs were synthesized by sulfonation and sulfation of polystyrene, leading to microgels and latexes. Both polymeric nanostructures affect the conformation of Aß inducing an unordered state. Oligomerization was delayed and cytotoxicity reduced. The proper balance between hydrophilic moieties and hydrophobic chains seems to be an essential feature of effective NPs.

The formation of lipid bilayers on surfaces.

The adsorption of biological molecules at solid-liquid interfaces is growing in importance due to its application to a very broad range of fields. Biomimetic systems like phospholipid mono- or bilayers are used to study such adsorption processes in great detail. Here we show how the formation of a complete lipid bilayer by vesicle adsorption and rupture depends on the type of the surface used. Fairly smooth SiO(2) surfaces and much rougher polyelectrolyte cushions are used to study this process. Depending on the chemical structure of the lipids, two different pathways are found on SiO(2) surfaces: either vesicle adsorption occurs in a first step until a critical coverage is reached followed by vesicle rupture and bilayer formation or adsorption and vesicle rupture occur almost at the same time. In the case of polyelectrolyte cushions, both neutron reflectivity and quartz crystal microbalance experiments show that the formation of homogeneous DMPC bilayers is significantly better on the negatively charged PSS surface compared to the positively charged PAH surface.