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Transmissibility of systemic amyloidosis by a prion-like mechanism
Katarzyna Lundmark1, Gunilla T Westermark, Sofia Nyström
1Division of Molecular and Immunological Pathology, Linköping University, 581 83 Linköping, Sweden.
Abstract:
The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this "amyloid enhancing factor" (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.
Insights
Amyloid fibrils form via a nucleation process. The amyloid enhancing factor (AEF) in AA amyloidosis is the AA fibril itself, which is potent and orally effective, suggesting transmissibility.
Area of Science:
- Biochemistry
- Pathology
- Immunology
Background:
- Amyloid fibril formation is a nucleation-dependent process.
- Amyloid Protein A (AA) amyloidosis in mice is accelerated by injecting tissue from affected animals.
- The chemical nature of the "amyloid enhancing factor" (AEF) has remained unidentified.
Purpose of the Study:
- To identify the active principle of AEF in AA amyloidosis.
- To characterize the potency and stability of AEF.
- To investigate the transmissibility of AA amyloidosis.
Main Methods:
- Extraction of AEF from spleen tissue of mice with silver nitrate-induced AA amyloidosis.
- Administration of AEF to mice to assess its biological activity.
- Evaluation of AEF potency and stability over time and via different administration routes.
Main Results:
- The active principle of AEF was unequivocally identified as the AA fibril itself.
- AEF demonstrated extreme potency, with activity observed at doses below 1 ng.
- AEF retained biological activity over extended periods and was effective when administered orally.
Conclusions:
- AA fibrils are the active component of AEF in AA amyloidosis.
- AA amyloidosis exhibits characteristics of a transmissible disease, similar to prion disorders.
- These findings have significant implications for understanding and potentially treating amyloidosis.