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Ultrastructural organization of hemodialysis-associated beta 2-microglobulin amyloid fibrils
1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Abstract:
Fibrils of hemodialysis-associated beta 2-microglobulin amyloid were examined by high resolution electron microscopy and immunohistochemical labeling. The amyloid containing tissues obtained through autopsy were prepared for thin section observations. In contrast to other forms of amyloid, the most conspicuous feature of these fibrils were their curved conformations. The fibril core showed ultrastructural and immunohistochemical features in common with the core of connective tissue microfibrils and of previously observed fibrils of experimental murine AA amyloidosis and familial amyloid polyneuropathy (FAP). The core was wrapped in a layer of 3 nm wide ribbon-like "double tracked" structures identified as chondroitin sulfate proteoglycan (CSPG) with immunogold labeling as well as from the results of previous in vitro experiments. Finally, the outer surface of the fibril was associated with a loose assembly of 1 nm wide filaments immunohistochemically identified as beta 2-microglobulin. This is similar to the manner in which AA protein and transthyretin filaments are associated with their respective fibrils. The results of this study provide an additional example for the concept that amyloid fibrils in general are microfibril-like structures externally associated with amyloid protein filaments. An unusual feature of the fibrils of hemodialysis-associated amyloid, however, is the presence of a peripheral layer composed of CSPG rather than of heparan sulfate proteoglycan (HSPG) as in the case of the other two amyloids above. These chondroitin sulfate chains in the outer CSPG layer may be less effective in providing rigidity to the fibril core, thus allowing for the curved conformations of beta 2-microglobulin amyloid fibrils.
Insights
Hemodialysis-associated amyloid fibrils composed of beta 2-microglobulin exhibit unique curved structures. These fibrils feature a core similar to other amyloids but are uniquely wrapped in chondroitin sulfate proteoglycans, influencing their conformation.
Area of Science:
- Biochemistry
- Pathology
- Microscopy
Background:
- Beta 2-microglobulin amyloidosis is a complication of long-term hemodialysis.
- Amyloid fibrils are protein aggregates implicated in various diseases.
- Understanding fibril structure is crucial for disease mechanism insights.
Purpose of the Study:
- To characterize the ultrastructure of hemodialysis-associated beta 2-microglobulin amyloid fibrils.
- To compare the structural features with other amyloid types.
- To elucidate the role of associated molecules in fibril morphology.
Main Methods:
- High-resolution electron microscopy of autopsy-derived amyloid tissues.
- Immunohistochemical labeling using specific antibodies.
- Analysis of fibril core and associated components.
Main Results:
- Beta 2-microglobulin amyloid fibrils display conspicuous curved conformations, unlike other amyloids.
- The fibril core shares features with connective tissue microfibrils and experimental amyloids.
- A distinct outer layer of chondroitin sulfate proteoglycan (CSPG) was identified, differing from heparan sulfate proteoglycan (HSPG) in other amyloids.
- Beta 2-microglobulin filaments were found on the outer surface.
Conclusions:
- Amyloid fibrils generally consist of a microfibril-like core with externally associated protein filaments.
- The CSPG layer in beta 2-microglobulin amyloid may contribute to its unique curved morphology.
- This finding expands the understanding of amyloid structure and diversity.