Apolipoprotein E allele-dependent pathogenesis: A model for age-related retinal degeneration

Abstract

Age-related macular degeneration (AMD) is a late-onset, multifactorial, neurodegenerative disease of the retina and the leading cause of irreversible vision loss in the elderly in the Western world. We describe here a murine model that combines three known AMD risk factors: advanced age, high fat cholesterol-rich (HF-C) diet, and apolipoprotein E (apoE) genotype. Eyes of aged, targeted replacement mice expressing human apoE2, apoE3, or apoE4 and maintained on a HF-C diet show apoE isoform-dependent pathologies of differential severity. ApoE4 mice are the most severely affected. They develop a constellation of changes that mimic the pathology associated with human AMD. These alterations include diffuse sub-retinal pigment epithelial deposits, drusenoid deposits, thickened Bruch's membrane, and atrophy, hypopigmentation, and hyperpigmentation of the retinal pigment epithelium. In extreme cases, apoE4 mice also develop marked choroidal neovascularization, a hallmark of exudative AMD. Neither age nor HF-C diet alone is sufficient to elicit these changes. We document choroidal neovascularization and other AMD-like ocular pathologies in an animal model that exploits known AMD risk factors. The model is additionally attractive because it is not complicated by invasive experimental intervention. Our findings in this model implicate the human apoE E4 allele as a susceptibility gene for AMD and support the hypothesis that common pathogenic mechanisms may underlie AMD and Alzheimer's disease.amyloid ͉ choroidal neovascularization ͉ macula ͉ retinal pigment epithelium ͉ cholesterol A ge-related macular degeneration (AMD) is the leading cause of irreversible vision loss in people over the age of 65, accounting for the majority of registered blindness in Western Europe and North America (1). A family of disorders, AMD is characterized by progressive loss of central, high-acuity vision due to dysfunction and death of photoreceptors (PRs) in the center of the retina, the macula. AMD pathology also impacts the retinal pigment epithelium (RPE, the cells responsible for support of PRs and maintenance of the choroidal blood-eye barrier), the choriocapillaris (CC, the primary capillary bed of the choroid), and Bruch's membrane (BrM, a stratified extracellular matrix between the RPE and the CC). Early AMD is characterized by moderate vision loss associated with characteristic extracellular lesions that form between the RPE and BrM. These lesions can be focal (drusen) or diffuse (basal deposits) (2-4). Late AMD is subdivided into two forms, dry or wet. Dry (geographic atrophy) is characterized by PR loss causing severe visual impairment concomitant with extensive RPE atrophy, whereas wet (exudative) features the sequela of choroidal neovascularization (CNV, i.e., in growth of the CC through BrM and under the RPE in the plane of drusen and basal deposits) (5).AMD is a complex disease in which the contributions of many genetic and environmental factors are confounding. The strongest known risk factor for AMD is advanced age, with the ri...

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

“…1). Interestingly, it has been recently reported that LRP6 variants are associated with increased fracture risk in men (58) and also with age-related macular degeneration (59); both conditions are frequently found in the elderly and may share common pathological mechanisms with AD (60).…”

Vascular endothelial growth factor in eye disease

“…Clinically, a number of studies have also reported the association of dietary fats with AMD (Chong et al, 2006). Cholesterol and apoE make up sub-RPE deposits in AMD eyes (Curcio et al, 2005;Li et al, 2006a), and Apo-E4 targeted replacement mice on high fat and cholesterol rich diets developed drusen and CNV (Malek et al, 2005). However, the connection between dietary fat, lipids, and VEGF is less clear.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Likewise, common LRP6 variants showed evidence both for linkage and association with agerelated macular degeneration (Haines et al, 2006). Therefore, given that both conditions are frequent in the elderly and may share common pathological mechanisms with AD (Malek et al, 2005), it is possible that these genetic variants may also have a role in determining susceptibility to develop AD. Further studies are needed to determine whether such variants display differential Wnt signaling activity.…”