Unraveling the in vivo Effect of the AMD-risk Associated CFH H402 Variant

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2018

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Abstract

Age-related macular degeneration (AMD) is a complex retinal degeneration present in elderly populations of first world countries with limited available therapeutic interventions. Risk for AMD is strongly conferred by advanced aging but is also modulated by genetic variants and environmental stresses. One of the most replicated genetic variants associated with AMD is the Complement Factor H (CFH) Y402H polymorphism. CFH is a critical regulator of the complement cascade but how the H402 variant impairs its function and contributes to AMD development is unclear. Herein, the role of the H402 variant in the development of AMD-like pathologies was interrogated using two different mouse models based on advanced aging, CFH perturbation and environmental stress.

First, aged CFH hemizygous knockout (Cfh+/-) mice were fed a high fat, cholesterol-enriched (HFC) diet for eight weeks to induce AMD-like pathologies such as vision loss, increased retinal pigmented epithelium (RPE) damage, increased sub-RPE deposit formation and immune cell recruitment to the RPE/choroid interface. To determine if the recruitment of immune cells drives the formation of the AMD-like pathologies in aged Cfh+/-~HFC mice, aged Cfh+/- mice were concurrently treated with a systemic anti-C5a therapy during the eight week HFC diet treatment to block the complement-mediated recruitment of immune cells to the eye. However, the ocular phenotype was unchanged in aged Cfh+/-~HFC mice treated with the anti-C5a therapy despite the decrease of recruited immune cells to the posterior eye. This data suggests the risk associated with the H402 CFH variant is not solely attributable to complement-mediated immune cell recruitment to the posterior eye.

Second, aged transgenic mice expressing equal concentrations of the normal human CFH Y402 (CFH-Y:Cfh-/-) or risk-associated CFH H402 (CFH-HH:Cfh-/-) protein were fed an eight week HFC diet. Remarkably, vision loss, increased RPE damage and increased sub-RPE deposit formation was only observed in aged CFH-HH:Cfh-/- mice following diet treatment. Biochemical analysis of aged CFH:Cfh-/- mice revealed differences in plasma and ocular lipoproteins, but not complement, between aged CFH-Y:Cfh-/-~HFC and CFH-HH:Cfh-/-~HFC mice. Thus, we targeted plasma lipoprotein levels through dietary intervention in aged CFH-HH:Cfh-/- mice and observed visual loss in these mice that coincided with dietary cholesterol-induced increases of plasma LDL. Based on our findings we hypothesize that the risk-associated with the H402 CFH variant and AMD is due to the interaction of CFH with lipoproteins and not its complement regulatory roles. These new insights may help explain why current therapies targeting complement inhibition for AMD have failed and, importantly, support targeting lipoprotein metabolism, as a treatment for AMD.

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Landowski, Michael (2018). Unraveling the in vivo Effect of the AMD-risk Associated CFH H402 Variant. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/17509.

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