Ream bound to high density lipoproteins. Under inflammatory conditions and interleukin-1 and -6 and tumor necrosis factor stimulation, the expression of these acute phase proteins is increased up to 1000-fold. During chronic inflammation such as rheumatoid arthritis, high concentrations of SAA eventually lead to the formation of a nucleus and polymerization of otherwise soluble SAA proteins into amyloid fibrils. Deposits of SAA fibrils can be found in the interstitial space of many organs. Similar to prion protein misfolding, this SAA fibrillation involves a conformational shift of SAA protein into a -sheet structure followed by aggregation. Mouse models of experimental AA-amyloidosis develop systemic amyloid deposits under chronic inflammatory conditions triggered by the intravenous, intraperitoneal or oral application of SAA-containing tissue or circulating blood monocytes derived from murine SAA mouse models. This process is reminiscent of transmissible prion diseases (Axelrad et al. 1982; Werdelin and Ranlov 1966). The “seeding” factor, also termed amyloid-enhancing factor (AEF), has been shown to consist in either SAA oligomers or SAA fibrils (Lundmark et al. 2002; Senthilkumar et al. 2008; Sponarova et al. 2008). Tasaki et al. (2010) haveCell Tissue Res (2013) 352:33demonstrated that blood and plasma derived from experimental murine SAA amyloidosis models can induce pathology in recipient animals and that freeze-thaw cycles abolish the seeding activity of these plasma samples.Alectinib The authors have been able not only to show that plasma EMVs isolated from mice with SAA amyloidosis carry oligomeric and prefibrillar SAA but also that these EMVs are sufficient to transmit disease pathology to recipient animals (Tasaki et al.Fengycin 2010).PMID:24428212 Noteworthy, though, is that not all exosome preparations possess seeding capacity, which might be a result of shearing forces or the clumping of EMVs during the preparation process. Another possible explanation is that only EMVs derived from SAA-positive organs can induce amyloidosis in recipient mice and that these EMVs are not present in the plasma in sufficiently high numbers all the time. An oral transmission of SAA amyloidosis among cheetahs, which secrete SAA fibrils in their faeces, has been reported (Zhang et al. 2008). Potentially infectious SAA fibrils have also been detected in foie gras (Solomon et al. 2007). Several lines of evidence point to an uptake of exogenous SAA amyloid seeds via the epithelial cells in Peyer’s plaques, followed by transepithelial transport, internalization into follicular dendritic cells and transfer to the spleen where amyloid replication and deposition occurs (for a review, see Westermark and Westermark 2009). This itinery most likely reflects a selective targeting pathway rather than random uptake and release of free circulating fibrils. The exosomal transfer of SAA aggregates could help to explain this reproducible route of seed propagation attributable to tissue- or cellspecific uptake signals on the surface of EMVs. Similar to transmissible prion diseases, cells from the lymphomoncytic lineage could mediate amyloid transport by the uptake of SAA-positive EMVs via specific receptors, followed by transport within the circulation and release through another round of exocytosis in the target tissue. In support of this notion, macrophages have been shown in vitro to be able to internalize AEF from the culture medium and SAA has been detected in various endocytic compartmen.
