Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers
Volker Luibl, … , Ralf Langen, Jeannie Chen
Volker Luibl, … , Ralf Langen, Jeannie Chen
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):378-385. https://doi.org/10.1172/JCI25843.
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Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers

Abstract

Protein misfolding and aggregation are thought to underlie the pathogenesis of many amyloid diseases, such as Alzheimer and Parkinson diseases, whereby a stepwise protein misfolding process begins with the conversion of soluble protein monomers to prefibrillar oligomers and progresses to the formation of insoluble amyloid fibrils. Drusen are extracellular deposits found in aging eyes and in eyes afflicted with age-related macular degeneration (AMD). Recent characterizations of drusen have revealed protein components that are shared with amyloid deposits. However, characteristic amyloid fibrils have thus far not been identified in drusen. In this study, we tested the hypothesis that nonfibrillar oligomers may be a common link in amyloid diseases. Oligomers consisting of distinct amyloidogenic proteins and peptides can be detected by a recently developed antibody that is thought to recognize a common structure. Notably, oligomers exhibit cellular toxicity, which suggests that they play a role in the pathogenesis of neurodegenerative diseases. Through use of the anti-oligomer antibody, we came to observe the presence of nonfibrillar, toxic oligomers in drusen. Conversely, no reactivity was observed in age-matched control eyes without drusen. These results suggest that amyloid oligomers may be involved in drusen biogenesis and that similar protein misfolding processes may occur in AMD and amyloid diseases.

Authors

Volker Luibl, Jose M. Isas, Rakez Kayed, Charles G. Glabe, Ralf Langen, Jeannie Chen

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Figure 5

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Codistribution of amyloid oligomer cores and other known drusen componen...
Codistribution of amyloid oligomer cores and other known drusen components. (A, E, and I) Differential interference contrast images. (B–D, F–H, and J–L) Confocal fluorescence images; amyloid oligomer cores were labeled with fluorescein (green). (A and B) Both antigens were present in a large druse, wherein the amyloid oligomer core was enveloped within the HLA-DR reactive region (labeled with Texas red). (C and D) At higher magnification, it is clear that the amyloid oligomer core and HLA-DR reactive subdomain did not colocalize in these drusen. (C) In one instance, the HLA-DR reactive region, perhaps reflecting a dendritic cell process, was observed as originating from the choroid (Ch), coming in close proximity to the Bm, and contacting the condensation of vesicular structures that represent the amyloid oligomer core. (D) In another instance, HLA-DR reactivity was observed as encompassing the choroid, the Bm, and the druse. Within the druse, HLA-DR reactivity appeared to surround the oligomer core, with no indication of colocalization. Similarly, no colocalization was observed with vitronectin (F–H) or Aβ (J–L), both labeled with Texas red (red). Lipofuscin autofluorescence within RPE is also visualized in the Cy3 channel (red). Scale bars: 10 μm. Magnification, ×250 (E, F, I, and J), ×1,500 (G), ×1,000 (H), and ×2,000 (K and L).