Purpose.: To evaluate the potential role of the matrix metalloproteinase (MMP) system of Bruch's membrane in the pathology of age-related macular degeneration. Methods.: Free and bound pools of gelatinase activity in Bruch's membrane–choroid preparations were isolated by phosphate-buffered saline (PBS) and sodium dodecyl sulfate (SDS) extraction, respectively. Individual MMP species were separated by gelatin-substrate zymography and the levels were quantified by densitometric techniques. Altogether, 13 control (age range, 71–99 years) and 6 AMD (age range, 71–95 years) donor eyes were used. Results.: All the gelatinase components normally present in control samples were also present in AMD tissue without any significant differences in their molecular masses. Total levels (bound plus free) of active MMP2 and -9 were significantly reduced in AMD donors (P < 0.05). The decrease in active MMP2 may be attributable to a similar reduction in the level of free pro-MMP2, the precursor to the active form. Reduction in active MMP9 occurred despite a nearly 3.5-fold increase in free pro-MMP9. The high-molecular-mass gelatinases denoted by HMW1 and -2 and comprising homo- and heteropolymers of pro-MMP2 and -9 were also raised in AMD (P < 0.05). The sequestration of free pro-MMP2 and -9 by these high-molecular-mass complexes may further contribute to reduced rates of activation of MMPs. Conclusions.: The reduction in the levels of activated MMP2 and -9 may be responsible for impaired matrix degradation of Bruch's membrane, leading to the pathology associated with AMD. The degradation pathway is therefore a viable therapeutic target for future intervention.

Photoreceptor maintenance is dependent on effective delivery of nutrients from the choroidal circulation by way of the acellular Bruch’s membrane and the retinal pigment epithelium. Aging of Bruch’s membrane is associated with thickening, increased cross linking of fibers, and deposition of debris culminating in reduced porosity. The present study has investigated the effects of aging on the diffusional transport of eight amino acids across Bruch’s membrane in 19 human donors. Diffusion studies were carried out in Ussing chambers, and the amount of time-dependent transfer of amino acids across the preparation was quantified by reverse-phase high-performance liquid chromatography. Diffusion rates for all amino acids showed a significant linear decline with aging of donor. The importance of this reduction in delivery of amino acids is discussed with reference to both normal physiology and age-related macular degeneration.