title: Interaction of A2E with model membranes. Implications to the pathogenesis of age-related macular degeneration.
abstract: Deposition of a fluorophoric material, known as lipofuscin, in retinal pigment epithelium cells has been speculated to be one of the biomarkers of age-related macular degeneration. One of the fluorophores of lipofuscin has been characterized as A2E, a pyridinium bisretinoid. Its cationic nature along with two hydrophobic retinal chains suggests that it can disrupt the membrane integrity by its detergent-like activity and can thus cause cellular damage. With this notion, we studied in detail the interaction between A2E and the model membranes of different lipid compositions using fluorescence steady-state and fluorescence anisotropy measurements. A transition from vesicular to micellar structure occurred upon incorporation of A2E into the lipid bilayer. However, the A2E concentration at which this transition occurred depends on the lipid composition. A lipid mixture containing 10% phosphatidylserine (PS) (close to disc membrane PS content) behaved similarly to a lipid mixture having no PS. In contrast, vesicles containing 20% PS showed significantly different behavior. Membrane solubilization by A2E was also confirmed by vesicle leakage experiments. A2E also showed significant activity in liposome-mediated gene transfection. A lipid formulation containing 40% A2E and a helper lipid showed plasmid DNA transfection efficiency comparable to commercially available transfection reagents with no evidence of cytotoxicity. These results contribute to understanding the mechanism underlying the A2E-induced cellular dysfunction.
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: De
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
mesh_terms: D016880:Anisotropy; D004161:Diphenylhexatriene / Q000378:metabolism; D004338:Drug Combinations; D005453:Fluorescence; D006706:Homeostasis; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008055:Lipids; D008081:Liposomes; D008268:Macular Degeneration / Q000209:etiology; D008567:Membranes, Artificial; D008854:Microscopy, Electron; D010539:Permeability; D010714:Phosphatidylethanolamines; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014162:Transfection
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; C112040:A2-E (N-retinylidene-N-retinylethanolamine); D004338:Drug Combinations; D008051:Lipid Bilayers; D008055:Lipids; D008081:Liposomes; D008567:Membranes, Artificial; D010714:Phosphatidylethanolamines; D011726:Pyridinium Compounds; D012176:Retinoids; D004161:Diphenylhexatriene