AMD pathogenesis based on lipid deposition may answer questions

January 2, 2013

Chicago-New precursors to the endpoints of age-related macular degeneration (AMD), geographic atrophy, and neovascularization have been defined based on biology that might help investigators answer the recurring question: why do individuals with the same precursors have progression to one form of AMD or the other?

AMD pathogenesis based on lipid deposition may answer questions

Jan 2, 2013
By: Lynda Charters
Ophthalmology Times eReport

 

 

Chicago-New precursors to the endpoints of age-related macular degeneration (AMD), geographic atrophy, and neovascularization have been defined based on biology that might help investigators answer the recurring question: why do individuals with the same precursors have progression to one form of AMD or the other?

Christine Curcio, PhD, of the department of ophthalmology at the University of Alabama, Birmingham, said that question might possibly be answered better in the future.

Dr. Curcio noted that AMD is a multifactorial disease of the photoreceptor support system, the retinal pigment epithelium (RPE), and Bruch’s membrane in the choroid. Therefore, maintaining and restoring the health of Bruch’s membrane is a route to restoring the health of the RPE and photoreceptors. In association with this, aging is the biggest risk factor for AMD, and accumulation of stressors or triggers with aging can activate complement and immune systems or impair the intraocular regulators of the immune system.

Dr. Curcio proposed a unified theory of AMD pathogenesis based on lipid deposition at Retina Subspecialty Day during the American Academy of Ophthalmology annual meeting in Chicago. The theory hypothesizes that oil red O binding in Bruch’s membrane, which is the single biggest aging change in normal eyes, serves as a barrier to delivery of micronutrients to the RPE and photoreceptors and may be a source of lipids that can be peroxidized by free radicals into proinflammatory, proangiogenic, and cytotoxic compounds. This provides a cleavage plane for neovessels from the choroid growing under the RPE. This lipid deposition in Bruch’s  membrane may be a manifestation of the systemic process of perifibrous lipid deposition and the foundation for atherosclerosis, xanthoma, and lipid keratopathy, she explained.

Lipids are the biggest component of drusen, especially soft drusen, and are dominated by esterified cholesterol (oil red O). Lipoprotein particles accumulate in Bruch’s membrane with aging and form basolinear deposits. The RPE secretes apoB and E particles that are retained in Bruch’s membrane; the RPE expresses hallmark genes of a lipoprotein secretor and the apolipoproteins are localized to drusen. The lipoproteins come from multiple lipid sources; in Bruch’s membrane, the lipoprotein fatty acids resemble those from dietary sources.

Dr. Curcio also proposed that a parallel process takes place in the subretinal space where space-filling extracellular lesions with druse-like composition form. Genetic associations and the pathobiology align, she noted.

“There are now new precursors with potential for clinical intervention, including lipoprotein metabolism and modification and regulation of inflammation,” concluded Dr. Curcio. “This means that new treatments for pharmaceutical and dietary modulation of dyslipidemia can be retooled to restore Bruch’s membrane. Valid cell culture models are now emerging to test this.  Finally, in the clinic, genetic, environmental, and ocular risk factors can be developed for the AMD end stages that are better defined on the basis of the underlying biology. The biology of vision is indeed miraculous.”

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