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Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and͞or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Similar observations in Alzheimer's disease (AD) have lead to the hypothesis that chronic localized inflammation is an important element of AD pathogenesis, with significant neurodegenerative consequences. Accordingly, the amyloid beta (A␤) peptide, a major constituent of neuritic plaques in AD, has been implicated as a primary activator of complement in AD. Here we show that A␤ is associated with a substructural vesicular component within drusen. A␤ colocalizes with activated complement components in these ''amyloid vesicles,'' thereby identifying them as potential primary sites of complement activation. Thus, A␤ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD. C urrent theories of Alzheimer's disease (AD) pathogenesis include inflammatory processes as significant contributors to the disease process (1). Chronic local inflammation, including both direct and bystander cell damage attributable to complement-mediated attack, exacerbates the effects of primary AD pathogenic stimuli. Amyloid beta (A␤) has been implicated in activation of the complement cascade (2) and is a major component of AD plaques, where it colocalizes with activated complement components, the C5b-9 membrane attack complex (MAC), acute phase reactants, and other inflammatory mediators (3-5).New evidence suggests that a strikingly similar, chronic local inflammatory component is also associated with the formation of drusen, the age-related extracellular deposits that are often linked with age-related macular degeneration (AMD) (6-9). AMD is a retinal degenerative disease that leads to loss of central vision, and affects 5-10% of the population over 60 years of age. Drusen form between the basal surface of an epithelial monolayer derived from neuroectoderm that is known as the retinal pigmented epithelium (RPE), and a basement membrane complex called Bruch's membrane (Fig. 1). Small numbers of drusen are present in the eyes of many older individuals; however, numerous and͞or confluent drusen are associated clinically with geographic atrophy of the RPE (10) and with a significantly increased risk of ...

Background: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression.

Comprehensive exon microarrays with a simple intra-gene normalization algorithm were used to detect human tissue-specific alternative splicing events, suggesting significant expression outside of known exons and well annotated genes and a high frequency of alternative splicing events.

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