Mechanical properties of lipid bilayers and their role in amyloid formation

Lipid bilayers are the basic structural element of biological membranes. The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and nonspecific interactions. It has been hypothesized that a potential pathway for Aβ toxicity may lie in its ability to modulate lipid membrane function. This hypothesis is based on the observation that Aβ bears a portion of the APP transmembrane domain. Thus, elucidating the interaction between Aβ and membrane lipids could be critical in understanding potential pathways of Aβ toxicity, especially given the results of studies that demonstrate that changes in membrane composition occur in AD along with the association with plaques, tangles, and neuritic dystrophy.

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Several physicochemical interactions underlie the ability of lipid membranes to facilitate protein aggregation and fibril formation, including increased protein accumulation at lipid-water interfaces, lipid induced protein conformational changes, protein orienting effects of lipid bilayers, modulation of nucleation propensities, and templating effects of membranes. Once Aβ aggregation begins in or near a membrane, the potential toxic mechanism include disruption of the bilayer structure, changes in bilayer curvature, and/or the creation of membrane pores or channels. Several studies have demonstrated that the presence of GM1 ganglioside enhance Aβ affinity for membrane surfaces and can play a critical role by causing structural changes, aggregation, and fibrillization of the peptide. The majority of studies on membrane-mediated fibrillogenesis have been undertaken with model systems including amyloidogenic peptides or proteins and lipid vesicles or supported bilayers of varying composition.

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Furthermore, the biochemical changes introduced by point mutation in Aβ may alter these peptide/lipid interactions. Thus, elucidating the direct interaction of mutant Aβ with lipids and lipid membranes may prove critical in understanding AD pathology. This will be accomplished through direct observations of mutant Aβ aggregation on supported lipid bilayers with the aid of in situ atomic force microscopy (AFM), followed by quantitative analysis of AFM images and the indirect measurement of bilayer mechanical properties that have been shown to influence the insertion of Aβ peptides into such model membranes. Analysis of bilayer mechanical properties will be accomplished with the recently developed scanning probe acceleration microscopy (SPAM), a variation of tapping mode AFM.

Figure: (A)Height and (B) phase TMAFM images of a 2:2:1 mixture ofDOPC:SpM:Chol lipid bilayer patches on mica.