Lipoprotein(A) with An Intact Lysine Binding Site Protects the Retina From an Age-Related Macular Degeneration Phenotype in Mice (An American Ophthalmological Society Thesis)

• Published in: Transactions of the American Ophthalmological Society 2015, Vol.113, p.T5-T5
• Main Authors: Handa, James T, Tagami, Mizuki, Ebrahimi, Katayoon, Leibundgut, Gregor, Janiak, Anna, Witztum, Joseph L, Tsimikas, Sotirios
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Apolipoproteins A - metabolism; Apolipoproteins B - metabolism; Binding Sites; Disease Models, Animal; Female; Humans; Immunohistochemistry; Lipoprotein(a) - metabolism; Lysine - metabolism; Macula Lutea - metabolism; Macular Degeneration - metabolism; Macular Degeneration - physiopathology; Male; Mice; Mice, Transgenic; Middle Aged; Oxidation-Reduction; Oxidative Stress - physiology; Phenotype; Phospholipids - metabolism; Retina - metabolism
• ISSN: 0065-9533; 1545-6110

To test the hypothesis that the accumulation of oxidized phospholipids (OxPL) in the macula is toxic to the retina unless neutralized by a variety of mechanisms, including binding by lipoprotein(a) [Lp(a)], which is composed of apolipoprotein(a) [apo(a)] and apolipoprotein B-100 (apoB). Human maculas and eyes from two Lp(a) transgenic murine models were subjected to morphologic, ultrastructural, and immunohistochemical analysis. "Wild-type Lp(a)" mice, which express human apoB-100 and apo(a) that contains oxidized phospholipid, and "mutant LBS(-) Lp(a)" mice with a defective apo(a) lysine binding site (LBS) for oxidized phospholipid binding, were fed a chow or high-fat diet for 2 to 12 months. Oxidized phospholipid-containing lipoproteins were detected by immunoreactivity to E06, a murine monoclonal antibody binding to the phosphocholine headgroup of oxidized, but not native, phospholipids. Oxidized phospholipids, apo(a), and apoB accumulate in maculas, including drusen, of age-related macular degeneration (AMD) samples and age-matched controls. Lp(a) mice fed a high-fat diet developed age-related changes. However, mutant LBS(-) Lp(a) mice fed a high-fat diet developed retinal pigment epithelial cell degeneration and drusen. These changes were associated with increased OxPL, decreased antioxidant defenses, increased complement, and decreased complement regulators. Human maculas accumulate Lp(a) and OxPL. Mutant LBS(-) Lp(a) mice, lacking the ability to bind E06-detectable oxidized phospholipid, develop AMD-like changes. The ability of Lp(a) to bind E06-detectable OxPL may play a protective role in AMD.