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L.V. Johnson, K.C. Talaga, A.J. Rivest, M.K. Staples, M.J. Radeke, E. Barron, D.H. Anderson; Characterization of Beta Amyloid-containing Vesicles within Drusen . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4229.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Numerous neurodegenerative disorders are characterized by protein aggregates that contribute significantly to disease pathogenesis. Despite differences in composition, it appears that similar pathologic mechanisms, including inflammatory processes, are responsible for their formation. Drusen contain a variety of proteins related to the process of inflammation or its aftermath. Recently, we reported that substructural vesicular elements within drusen contain amyloid beta peptide, a major pro-inflammatory component of Alzheimer's disease (AD) plaques. To assess the potential significance of these "amyloid vesicles" in drusen formation and in the pathogenesis of age-related macular degeneration, we further characterized their ultrastructural organization and protein composition. Methods: Immunogold electron microscopy was employed to examine ultrastructural organization and substructural distribution of beta amyloid and other drusen-associated molecules. Confocal immunofluorescence microscopy was used to determine whether the vesicles contain additional proteins characteristic of AD plaques or other disease-associated deposits. Quantitative RT-PCR (QPCR) assays were utilized to assess potential biosynthetic sources of these proteins. Results: Amyloid vesicles are multilamellar structures with an electron dense outer shell, and an inner core with an intervening electron lucent layer containing flocculent material. Amyloid beta immunoreactivity is concentrated in the outermost shell that is composed of densely packed fibrils. Other prominent drusen-associated proteins including vitronectin, apolipoprotein E, amyloid P component, and ubiquitin are excluded from the vesicles. Subpopulations of amyloid vesicles contain additional amyloid-related proteins, including transthyretin, thrombin, alpha-synuclein, and alpha B-crystallin. These molecules may either co-localize with amyloid beta or distribute in different vesicular compartments. QPCR assays show that RPE cells are capable of synthesizing transcripts for each of these molecular constituents. Conclusions: Amyloid vesicles are unique macromolecular protein aggregates that may be a potent pro-inflammatory stimulus in the context of drusen formation. Their presence is an additional indication that some of the pathogenic pathways that give rise to drusen are shared with other neurodegenerative diseases characterized by abnormal protein aggregation and deposition.
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