The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.

Background: The deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD.

Inhibiting host-pathogen interactions using membrane-based nanostructures.

Virulent strains of bacteria and viruses recognize host cells by their plasma membrane receptors and often exploit the native translocation machinery to invade the cell. A promising therapeutic concept for early interruption of pathogen infection is to subvert this pathogenic trickery using exogenously introduced decoys that present high-affinity mimics of cellular receptors. This review highlights emerging applications of molecularly engineered lipid-bilayer-based nanostructures, namely (i) functionalized liposomes, (ii) supported colloidal bilayers or protocells and (iii) reconstituted lipoproteins, which display functional cellular receptors in optimized conformational and aggregative states.

pH responsive polymer cushions for probing membrane environment interactions.

A robust and straightforward method for the preparation of lipid membranes upon dynamically responsive polymer cushions is reported. Structural characterization demonstrates that complete, well-packed membranes with tunable mobility can be constructed on the polymeric cushion. With this system, membrane conformational changes induced by cellular cytoskeleton interactions can be modeled.

Reconstituted lipoprotein: a versatile class of biologically-inspired nanostructures.

One of biology's most pervasive nanostructures, the phospholipid membrane, represents an ideal scaffold for a host of nanotechnology applications. Whether engineering biomimetic technologies or designing therapies to interface with the cell, this adaptable membrane can provide the necessary molecular-level control of membrane-anchored proteins, glycopeptides, and glycolipids. If appropriately prepared, these components can replicate in vitro or influence in vivo essential living processes such as signal transduction, mass transport, and chemical or energy conversion.

A differential association of Apolipoprotein E isoforms with the amyloid-β oligomer in solution.

The molecular pathogenesis of disorders arising from protein misfolding and aggregation is difficult to elucidate, involving a complex ensemble of intermediates, whose toxicity depends upon their state of progression along distinct processing pathways. To address the complex misfolding and aggregation that initiates the toxic cascade resulting in Alzheimer's disease (AD), we have developed a 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid spin-labeled amyloid-β (Aβ) peptide to observe its isoform-dependent interaction with the apoE protein. Although most individuals carry the E3 isoform of apoE, ∼15% of humans carry the E4 isoform, which is recognized as the most significant genetic determinant for Alzheimer's.

Lactosomes: structural and compositional classification of unique nanometer-sized protein lipid particles of human milk.

Milk fat globules (MFGs) are accepted primarily as triacylglycerol delivery systems. The identification of nanometer-sized lipid-protein particles termed "lactosomes" that do not contain triacylglycerol raises the question of their possible functions. MFGs were isolated by slow centrifugation, and lactosomes were isolated by ultracentrifugation at a density equivalent to plasma high-density lipoproteins (HDL) (d > 1.

Ganglioside embedded in reconstituted lipoprotein binds cholera toxin with elevated affinity.

The ability to exogenously present cell-surface receptors in high-affinity conformations in a synthetic system offers an opportunity to provide host cells with protection from pathogenic toxins. This strategy requires improvement of the synthetic receptor binding affinity against its native counterpart, particularly with polyvalent toxins where clustering of membrane receptors can hinder binding. Here we demonstrate that reconstituted lipoprotein, nanometer-sized discoidal lipid bilayers bounded by apolipoprotein and functionalized by incorporation of pathogen receptors, provides a means to enhance toxin-receptor binding through molecular-level control over the receptor microenvironment (specifically, its rigidity, composition, and heterogeneity).

Frustrated phase transformations in supported, interdigitating lipid bilayers.

In free bilayers, the fluid to gel main phase transition of a monofluorinated phospholipid (F-DPPC) transforms a disordered fluid bilayer into a fully interdigitated monolayer consisting of ordered acyl tails. This transformation results in an increase in molecular area and decrease in bilayer thickness. We show that when confined in patches near a solid surface this reorganization proceeds under constraints of planar topography and total surface area.

Bridging across length scales: multi-scale ordering of supported lipid bilayers via lipoprotein self-assembly and surface patterning.

We show that a two-step process, involving spontaneous self-assembly of lipids and apolipoproteins and surface patterning, produces single, supported lipid bilayers over two discrete and independently adjustable length scales. Specifically, an aqueous phase incubation of DMPC vesicles with purified apolipoprotein A-I results in the reconstitution of high density lipoprotein (rHDL), wherein nanoscale clusters of single lipid bilayers are corralled by the protein. Adsorption of these discoidal particles to clean hydrophilic glass (or silicon) followed by direct exposure to a spatial pattern of short-wavelength UV radiation directly produces microscopic patterns of nanostructured bilayers.