Abstract
Purpose :
To clarify the mechanism of dysregulation in ATP-binding cassette transporter A1 (ABCA1) for the pathogenesis of glaucoma.
Methods :
Experiments were performed using DBA/1J (wild type, WT) and ABCA1 deficient (KO) mice. Gfap-Cre::flox/floxABCA1 and Gfap-Cre mice were used as astrocyte-specific ABCA1KO (Astro-cKO) and control mice, respectively. Intraocular pressure (IOP) was measured using a rebound tonometer. The number of retinal ganglion cells (RGCs) in the whole-mount retina was estimated by labeling them with an anti-Brn3a antibody. TdT-mediated dUTP nick end labeling (TUNEL) was performed to detect apoptotic cells. To investigate the complexity of RGC dendrites, the mice were crossed with Thy1-GFP mice to visualize their morphologies. For a detailed analysis of the optic nerve, we used serial block-face scanning electron microscopy (SBF-SEM). The ocular function was evaluated using a multifocal electroretinogram (mfERG).
Results :
ABCA1KO mice showed no IOP elevation, reduction in RGC number, and an increase in apoptotic cells at 12 months old but not at 3 months old. ABCA1 signals were localized at the nerve fiber layer and co-localized with GFAP but not with vimentin signals, indicating predominant expression in astrocytes. Astro-cKO mice showed age-associated RGC degeneration without IOP elevation, atrophy of dendritic arbor of RGCs, thinning of retinal layers, axonal swelling, and impaired ocular function.
Conclusions :
These data suggest that loss of function of ABCA1 is essential for glaucoma, especially astrocytic ABCA1 is important and triggers normal-tension glaucoma-like phenotype in mice.
This is a 2021 ARVO Annual Meeting abstract.