We have shown that the β1 subunit of integrins partially mediate the adherence of human RPE cells to RPE-derived extracellular matrix and the basal lamina layer of human Bruch’s membrane.
18 Recently, it has been shown by immunoprecipitation experiments in carcinoma-derived cell lines that CD46 associates with multiple β1 integrins
19 and indirectly with a superfamily of surface molecules,
37 tetraspanin, known also to associate with a subset of β1 integrins
38 39 40 41 and to form a web with common functions related to migration, proliferation, intracellular signaling and adhesion.
42 43 44 45 46 CD46 is a newly discovered component of this web.
19 The relevance of these protein associations to RPE cells is that they may form the functional units underlying normal adhesion mechanisms, maintaining a healthy RPE phenotype that is not proliferative or migratory. When there is disease, these functional units may become disrupted, the RPE may lose attachment to Bruch’s membrane, and RPE cells may break away from the monolayer and undergo apoptosis.
47 Therefore, the loss of RPE cells, which is one of the first signs of AMD,
48 may be preceded by the loss of RPE attachment to Bruch’s membrane through a dysfunctional CD46–β1 integrin complex. A recent study, in which flatmount preparations of human cadaveric eyes were stained with the TUNEL technique, provides direct evidence that human RPE undergoes age-related apoptosis in situ, with apoptotic human RPE confined mainly to the macula of older human eyes.
49 Another similar report suggests that human RPE die by apoptosis around the edges of geographic atrophy.
50 Secondary atrophy of the underlying choriocapillaris and overlying photoreceptors would then follow and signal the clinical recognition of AMD. More studies are needed to determine how specific molecular interactions of integrin with CD46 and other protein partners play a role as a functional unit in maintaining RPE adhesion and phenotype.