Abstract
Purpose :
The primary risk factor for the blinding disease age-related macular degeneration (AMD) is aging; other factors include genetic variants, diet, lifestyle, and environmental exposures. The most effective AMD animal models incorporate multiple risk factors to determine the individual and combined risk for AMD-like disease. This repeated measures study tested the hypothesis that heterozygosity of peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (Pgc1a) and aging in mice is sufficient to cause vision and retinal structure/function deficits akin to early AMD.
Methods :
Mice heterozygous for Pgc1a knockout mutation (+/-) were obtained (Jax.org, #8597) and bred to produce Pgc1a +/- and +/+ mice. We measured vision by optomotry (OMR; scotopic sc, photopic ph), dark- and light-adapted (DA, LA) electroretinography (ERG) a- and b-wave amplitude and peak time, flicker amplitude, and retinal thickness by optical coherence tomography (OCT) at 6- and 24-months-old. A subset of mice (n=3-4/group) at 6- and 24-months were euthanized and underwent posterior eyecup RNA sequencing and retinal pigment epithelium (RPE) electron microscopy (EM). A mixed-effects statistical model was applied with Prism 9.
Results :
Young Pgc1a +/- mice had reduced OMR indexes (sc P=.0001, ph P=.0005, n=12/group), but equivalent DA and LA ERG amplitudes (sc P=.43-.99, ph P=.17-.39, n=12-13/group). 24-month +/- mice had reduced DA a-wave and b-wave amplitudes (P=.04 and .03), delayed peak times (P=.007 and .001), and reduced rod 5Hz flicker amplitudes (P=.008, n=7-10/group). There were no differences in LA ERG (P=.25-.96) or retinal thickness. The greatest gene expression effects were at 24-months in the RPE/choroid/sclera, with most significantly differentially expressed genes downregulated. EM at 24-months showed melanolipofuscin accumulation, defective phagosome degradation, basal laminar deposits, and constriction of the choriocapillaris.
Conclusions :
Early AMD-like histologic features are associated with rod dysfunction in aged Pgc1a +/- mice. Pgc1a, highly expressed in the human outer retina, is critical to rod maintenance, RPE phagocytosis, mitochondrial dynamics, and oxidative stress mitigation. Combining this phenotype with additional AMD risk factors, like a western diet, may even better approximate human AMD’s natural multifactorial etiology and allow study and treatment of AMD in its subclinical and early stages.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.