**9. ABCA1, Age-Related Macular Disease and Glaucoma**

Age-related macular degeneration (AMD) is a leading cause of visual impairment and severe vision loss in individuals above 50 years of age. AMD is a multifactorial and complex disorder, where immunological factors, inflammation, lipid and cholesterol metabolism, angiogenesis and extracellular matrix are involved in the disease pathogenesis [270]. Early disease is characterized by the presence of cholesterol-rich extracellular deposits similar to atherosclerotic plaques underneath the retinal pigment epithelium (RPE) or in the subretinal space, called drusen or drusenoid deposits [271–276], which may lead to atrophic neurodegeneration or pathologic angiogenesis. Drusen contain polar lipids such as free cholesterol and phosphatidylcholine, as well as neutral lipids such as cholesteryl esters and apolipoproteins [277]; while drusenoid deposits seem to contain only free cholesterol and apolipoproteins [278].

Several lines of evidence suggest that cholesterol metabolism and ABCA1 are involved in AMD pathogenesis. Systemic disturbances in cholesterol metabolism causing altered lipoprotein subtype levels have been associated with AMD [279]. Moreover, while retinal abnormalities have not been reported in Tangier disease, GWAS and candidate gene studies have shown that *ABCA1* gene variation contributes to AMD susceptibility, although to a lesser degree than the complement factor H (*CFH*) Y402H and age-related macular susceptibility-2 (*ARMS2*) A69S polymorphisms, which are well established risk factors for AMD [280–285]. In addition, human RPE cells express *ABCA1* and other genes involved in lipid metabolism such as *SRBI*, and glyburide-mediated inhibition of ABCA1 and SRBI activity was found to abolish HDL-stimulated basal efflux of photoreceptor-derived lipids in cultured human RPE cells, supporting a role of RCT regulation in the pathogenesis of AMD [286]. Finally, murine KO models also support the role of ABCA1 and cholesterol metabolism in AMD pathogenesis. Targeted deletion of macrophage *Abca1* and *Abcg1* in mice led to age-associated extracellular cholesterol-rich deposits underneath the neurosensory retina similar to the drusenoid deposits observed in early stages of human AMD, and the mice developed impaired dark adaptation and rod photoreceptor dysfunction [287,288].

Glaucoma is the world's leading cause of irreversible blindness [289]. It is a degenerative optic neuropathy characterized by the progressive degeneration of retinal ganglion cells (RGC) and the retinal nerve fiber layer (RNFL), leading to visual impairment and eventually to blindness. Elevated intraocular pressure (IOP) is a major risk factor for most types of glaucoma. Primary open-angle glaucoma (POAG) is characterized by increased resistance to aqueous fluid outflow through the trabecular meshwork and is the most common form of glaucoma worldwide. Primary angle-closure glaucoma is caused by blocked access to the outflow tracks; and secondary exfoliation glaucoma is a sequela of exfoliation syndrome characterized by accumulation of a characteristic fibrillar material on the ocular lens and trabecular meshwork [290]. Mendelian forms of glaucoma are caused by mutations in *MYOC*, *OPTN* and *TBK1* genes [291]. However most cases of glaucoma are multifactorial, and various biological processes including lipid metabolism, cytokine signaling, membrane biology, extracellular matrix, fucose and mannose metabolism, cell and ocular development are involved in the pathophysiology of the disease.

Several lines of evidence including GWAS, animal models and in vitro studies suggest ABCA1 plays an important role in the pathophysiology of glaucoma, mainly POAG. Although glaucoma is not a characteristic of Tangier disease, GWAS for IOP and POAG have identified common variants in or near *ABCA1* (rs2472493 and rs2487032) among more

than 50 loci in Asian and European Caucasian populations [292–295]. However, while ABCA1 and other genes involved in lipid metabolism were found to be associated with IOP and POAG, a Mendelian randomization study did not find any evidence for a causal association between plasma lipid levels and POAG risk [296].

*ABCA1* is highly expressed in retinal ganglion cells and its expression is significantly higher in individuals with glaucoma and upregulated in high-IOP glaucoma murine models. This suggests that ABCA1 is involved in the normal biological functions and cell death of ganglion cells. A recent study reported evidence of a novel role for ABCA1 in IOP modulation via the regulation of the Cav1/eNOS/NO signaling, which is likely to be an important mechanism of pathogenesis in patients with POAG. Based on their findings, the authors suggest that enhancing the ABCA1 signaling pathway could be of therapeutic value in the treatment of glaucoma and ocular hypertension [297].
