Bruch's membrane. A normally functioning Bruch's membrane is sufficiently permeable to allow diffusional exchange of nutrition and waste products between the choroidal capillaries and RPE cells.
AMD is a chronic disease resulting from a malfunctioning of this system at several loci. Although there are many gaps in understanding of the disease pathology and progression, a general hypothesis with several variations has emerged, based on consistent clinical and epidemiologic observations in AMD patients.2'15 Dry AMD is characterized by increased deposition of a material called ldmsen\ which can be observed clinically using an ophthalmoscope, between the RPE and Bruch's membrane. Drusen likely originate from material discharged from RPE cells. Although this process probably occurs throughout life due to the heavy phagocytosis burden of RPE cells, the composition of the material expelled from dying/dysfunctional cells may be more heavily weighted toward injurious components such as oxidized lipids, proinflammatory cytokines, and acute phase inflammatory proteins.16 Intriguingly, it has recently been reported that drusen commonly contain amyloid beta, a proinflammatory protein associated with protein misfolding and neurodegenerative pathology in Alzheimer's disease (see 6.08 Neurodegeneration).17 The more highly cytotoxic composition of drusen derived from dying RPE cells may itself induce inflammation-induced oxidative stress, increased RPE cell death, and the formation of yet more drusen in a positive feedback loop.18 Consequently, photoreceptor cell death occurs, since photoreceptors cannot survive without their supporting RPE cells. The loss of macular photoreceptors is termed 'geographic atrophy'. Without functioning macular photoreceptors, central visual acuity is gradually lost.
Although it is widely accepted that RPE cell dysfunction plays a central role in AMD disease progression, the complex interaction of the RPE with photoreceptors, Bruch's membrane, and the choroidal blood supply have made it difficult to unentangle the cause and effect of RPE cell death. Cell dysfunction likely begins with intralysosomal accumulation of a fluorescent material called lipofuscin. Lipofuscin is a complex mixture rich in polyunsaturates, and is probably derived from phagocytosed photoreceptor outer segments that are undigestible. Over time this material inactivates lysosomal enzymes and raises the pH level, causing lysosomal membrane breach and cell death. This process may be accelerated by efficient lipofuscin photon absorption and fluorescence to generate reactive oxygen species, which damages surrounding proteins and membranes.
A likely functionally important component of lipofuscin is the amphiphilic pyridinium ion A2E19 (Figure 3), that is believed to be formed in vivo from the condensation of one equivalent of phosphatidylethanolamine with two equivalents of 11-trans-retinaldehyde, followed by phospholipase-D-catalyzed dephosphorylation. A2E might be the major component of lipofuscin, producing reactive oxygen species (ROS).20 A2E is thought to be the major component of lipofucsin producing ROS in the presence of light and oxygen.20 Enhanced production of A2E can occur as the result of the dysfunctional transport of photobleached 11-trans retinal/phosphatidyethanolamine Schiff base (NRPE) through the photoreceptor disk membrane resulting in the accumulation of RPE cell lysosomes. BNRPE transport ossurs via an ABCR (ATP-binding cassette transporter) mechanism. Individuals null for the ABCR gene suffer from Stardgardt's macular dystrophy, an early-onset macular degeneration-like disease.21 Individuals with one allele of the ABCR gene may be at higher risk for developing AMD,22 but this is not a major risk factor.
What are the characteristics of dry AMD that cause progression to the wet form in susceptible patients? The answer to this question may lie in the consequences of RPE cell dysfunction. As mentioned above, continuous RPE cell discharge of intracellular material, such as oxidized lipids and proinflammatory proteins, leads to accumulation of this material in drusen between the RPE and Bruch's membrane, and deposition of this material within Bruch's membrane.
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