PGC-1α repression and high fat diet induce age-related macular degeneration-like phenotypes in mice

Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries and its prevalence is increasing with the aging population. AMD initially affects the retinal pigment epithelium (RPE) and gradually leads to secondary photoreceptor degeneration. Recent studies have associated mitochondrial damage with AMD, and we have observed mitochondrial and autophagic dysfunction and repressed peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α in native RPE from AMD donor eyes and their respective induced pluripotent stem cell-derived RPE (AMD RPE-iPSC-RPE). To further investigate the effect of PGC-1α repression we have established a mouse model by feeding PGC-1α + /- mice with high fat diet (HFD) and investigated the RPE and retinal health. Here we show that when mice expressing lower levels of Pgc-1α are exposed to HFD, they present AMD-like abnormalities in RPE and retinal morphology and function. These abnormalities include basal laminar deposits, thickening of Bruch9s membrane (BM) with drusen marker-containing deposits, RPE and photoreceptor degeneration, decreased mitochondrial activity, increased ROS levels, decreased autophagy dynamics/ flux, and increased inflammatory response in the RPE/retina. Our study show that the PGC-1α is important in outer retina biology and that PGC-1α + /- mouse fed with HFD is a promising model to study AMD and opens doors for novel treatment strategies in AMD.