Cfh genotype interacts with dietary glycemic index to modulate early age-related macular degeneration-like features in mice

Abstract

Purpose: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the aging population. Both genetics and diet contribute to the relative risk for developing AMD. Common variants in the Complement Factor H (CFH) gene confer susceptibility to or protection from developing AMD. Consuming higher glycemic index (GI) diets has been associated with increased AMD risk as well as with insulin resistance and CNS inflammation. Here, we explored the effects of dietary GI manipulation on development of early AMD-like features (eAMD-f) and changes to CNS inflammation in the Cfh-null mouse model of AMD.

Methods: Starting at 12-weeks of age, wildtype C57Bl6/J (WT) or Cfh-null mice were fed high or low GI diets for 33 weeks. At 10-months of age, mice were evaluated for eAMD-f in the neural retina and retinal-pigmented epithelium (RPE) by light (LM) or electron (EM) microscopy. Brains were analyzed for Iba-1 (macrophage/microglia) immunostaining, an indicator of inflammation.

Results: At 10-months of age, WT mice showed no eAMD-f on either diet, consistent with prior observations. Cfh-null mice, however, showed distinct eAMD-f in the RPE when fed a low GI diet, including vacuolation, disruption of basal infoldings, and increased numbers of basal laminar deposits (by EM). Cfh-null mice fed either diet also showed some thinning of the photoreceptor inner segment layer (by LM). The number of Iba-1+ macrophages was increased in brains of Cfh-null mice relative to WT mice, but there was no diet effect.

Conclusions: The presence of eAMD-f by 10-months of age in Cfh-null mice fed a low GI diet precedes the overt retinal phenotypes previously described in 2-year-old Cfh-null mice. This surprising result is in contrast to the apparent protection from eAMD-f observed in older (17- and 23-month) WT mice fed lower GI diets. Modulation of dietary GI did not appear to influence CNS inflammation. Our findings highlight the need to consider genetic/diet interactions when developing therapeutic approaches to treat AMD.

Keywords: 412 age-related macular degeneration • 618 nutritional factors • 555 immunomodulation/immunoregulation