Retinal and optic nerve degeneration in liver X receptor β knockout mice

Abstract

The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRβ, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRβ−/− mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aβ) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aβ in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRβ−/− mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of reduction in its expression.

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

“…Aβ accumulation has been identified in post-mortem studies in the retina, especially the GCL and ON in glaucoma patients and animal models ( Figure 1 and Figure 2 ) [ 1 , 66 , 67 , 68 ]. In murine models of glaucoma, Aβ was identified in TUNEL-positive RGC from both in vivo and in vitro studies indicating that Aβ directly induces an increase in caspase-3 expression leading to RGC apoptosis [ 69 , 70 , 71 ].…”

Selective LXR agonist DMHCA corrects retinal and bone marrow dysfunction in type 2 diabetes

“…LXR signaling plays an important role in inflammation and disease (30). In the retina, LXR depletion causes retinal/optic nerve degeneration (31), formation of acellular capillaries (18), and retinal pigment epithelial changes (32), suggesting that LXR is required for normal retinal maintenance and that its absence results in pathologies spanning the entire retina. Interestingly, in the diabetic retina, LXR expression is downregulated, and activation of LXR using a chemical agonist is sufficient to reduce gliosis and the formation of acellular capillaries (18,19).…”

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

“…Curiously, the onset of retinal dysfunction upon inhibition of cholesterol efflux at the level of LXRα/β, or ABC transporters (also CYP hydroxylase knockouts-discussed later) leads to a slow retinal degeneration phenotype that manifests by about 1 year. This is unlike inhibition of retinal de novo cholesterol biosynthesis either through statin treatment (which most likely is due to protein prenylation compromise, rather than blockade of sterol synthesis), or as observed in the AY9944induced model of SLOS (see below), which leads to retinal degeneration on a timescale of weeks (75,(130)(131)(132). In sum, these observations independently indicate significant differences in the rates of retinal sterol synthesis and turnover, in agreement with the results of previous studies (59,78).…”