Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterolenriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aβ40 and Aβ42. Concomitant reduction in the levels of Aβ and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aβ40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aβ antibodies. They also implicate Aβ in the pathogenesis of AMD and identify Aβ as a viable therapeutic target for its treatment.A ge-related macular degeneration (AMD) affects about 30% of Americans over 70 y of age (1-3) and is the leading cause of irreversible blindness in the Western world (4). It is a progressive retinal degenerative disease influenced by both environmental and genetic factors. Although the presence of a few small hard drusen is a normal, nonvision-impairing part of aging, the deposition of large diffuse drusen in the macula adversely impacts vision and is indicative of early AMD. As AMD progresses to late-stage disease, it is categorized as either dry [geographic atrophy with photoreceptor loss and extensive atrophy of the retinal pigmented epithelium (RPE)] or wet [exudative with subsequent choroidal neovascularization (CNV)] (5). Currently, there are no effective treatments for early AMD, and treatments for late-stage disease are limited to photodynamic therapy, macular translocation, and antivascular endothelial growth factor drugs (6-9).The strongest known risk factors are advanced age and cigarette smoking, with additional risk conferred by body mass index and diets high in fat (1,(10)(11)(12)(13)(14). The last decade has also yielded strong evidence that genotype, especially for genes involved in inflammation and the innate immune system, influences AMD risk and progression. Genes implicated as risk factors include complement factor H (CFH) (15-18), complement factor B (19), complement C3 (20), apolipoprotein E (APOE) (21-25), toll-like receptor 4 (26), LOC387715/ARMS2 (27, 28), HTRA1 (29, 30), ABCA4 (31), and fibulin 5 (32). Additional support for a role for chronic local inflammation in AMD comes from the discovery that protein components of drusen include activated co...

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

“…RPE cell-boundary disruptions and increased frequency of multinucleated RPE cells were seen in focal regions of flat mounts from AhR −/− mice. Notably, a similar pattern has been observed in RPE flat mounts from donor eyes with documented AMD (27).…”

Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta‐induced retinal degeneration

“…We have showed that subretinal injection of Ab(1-42) damages the RPE in young and old mice (Bruban et al, 2009): photoreceptors die by apoptosis within a few days and microglial cells phagocytize photoreceptor debris and Ab after subretinal injection of Ab(1-42) (Bruban et al, 2011). Anti-Ab antibody immunotherapy has recently been shown to protect against RPE damage and vision loss in a mouse model of age-related macular degeneration (Ding et al, 2011). The molecular processes and cellular events involved in photoreceptor cell death induced by Ab in the subretinal space nonetheless have yet to be elucidated.…”

Age-related macular degeneration and Alzheimer disease

“…As an example, the treatment modalities that have targeted Alzheimer disease might also be applied to AMD. Immunotherapy targeting amyloid-β has been proven effective in protecting the retinal pigment epithelium (69,70). Apolipoprotein E, which is speculated to rapidly degrade amyloid-β and reverse the effects of Alzheimer disease, may be targeted for the degradation of the drusen in AMD.…”