Abstract
The biophysical properties and biological functions of membranes are highly dependent on lipid composition. Supplementing cellular membranes with very long chain fatty acids (vlcFAs) is notoriously difficult given the extreme insolubility of vlcFAs in aqueous solution. Herein, we report a solvent-free, photochemical approach to enrich target membranes with vlcFA. To prevent aggregation of vlcFA, we created light-sensitive micelles composed exclusively of poly-ethylene-glycol-nervonic acid amphiphiles (NA-PEG), which spontaneously disassemble in the presence of lipid bilayers. Once embedded within a membrane, UV light is used to cleave off PEG, leaving free nervonic acid (NA, i.e. FA24:1) in the target membrane. When applied to living cells, free NA was processed by the cell to generate various species of membrane and other lipids with incorporated vlcFAs. In this way, we were able to alter the membrane lipid composition of cellular membranes and modulate the enzymatic activity of γ-secretase, an intramembrane protease whose dysfunction has been implicated in the onset and progression of Alzheimer's disease.
Highlights
Phospholipid bilayers, as the main constituent of cellular membranes, maintain the structural integrity of cells and are critically important to numerous cellular processes
By altering the lipid composition of cellular membranes in this way, we were able to modulate the enzymatic activity of γ-secretase leading to a reduction of the relative amount of toxic amyloid-β42 (Aβ42) peptides secreted by treated cells. γ-Secretase dysfunction, and the associated increase in the secretion of Aβ42 relative to Aβ40 peptides, is widely believed to contribute to the onset and progression of Alzheimer's disease [16,17]
Self-assembly of nervonic acid-PEG conjugate (NA-PEG) in aqueous media resulted in close-packed micelles of approximately 15 nm in size, as determined by dynamic light scattering (DLS, Fig. S4)
Summary
Phospholipid bilayers, as the main constituent of cellular membranes, maintain the structural integrity of cells and are critically important to numerous cellular processes. Once embedded in the plasma membrane, we hypothesized that delivered vlcFAs would be taken up into cellular compartments, enter membrane remodelling pathways [15] and be incorporated into cellular phospholipids This would, in turn, create larger hydrophobic domains within the lipid bilayer of the cellular membrane and potentially modulate membrane protein activity [3,4]. NA was chemically conjugated to poly-ethylene-glycol (PEG) via a photocleavable (o-nitrobenzyl) linker (NA-PEG, Fig. 1) to form vlcFA amphiphiles that self-assemble to close-packed micelles in aqueous media These micelles spontaneously disassemble in the presence of a lipid bilayer to embed NA-PEG within the target membrane (Fig. 1). By altering the lipid composition of cellular membranes in this way, we were able to modulate the enzymatic activity of γ-secretase leading to a reduction of the relative amount of toxic amyloid-β42 (Aβ42) peptides secreted by treated cells. By altering the lipid composition of cellular membranes in this way, we were able to modulate the enzymatic activity of γ-secretase leading to a reduction of the relative amount of toxic amyloid-β42 (Aβ42) peptides secreted by treated cells. γ-Secretase dysfunction, and the associated increase in the secretion of Aβ42 relative to Aβ40 peptides, is widely believed to contribute to the onset and progression of Alzheimer's disease [16,17]
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