Cross-Seeding and Cross-Competition in Mouse Apolipoprotein A-II Amyloid Fibrils and Protein A Amyloid Fibrils

Abstract

Murine senile [apolipoprotein A-II amyloid (AApoAII)] and reactive [protein A amyloid (AA)] amyloidosis are reported to be transmissible diseases via a seeding mechanism similar to that observed in the prion-associated disorders, although de novo amyloidogenesis and the progression of AApoAII or AA amyloidosis remain unclear. We examined the effect of co-injection of AApoAII and AA fibrils and multiple inflammatory stimuli in R1.P1-Apoa2(c) mice with the amyloidogenic Apoa2(c) allele. Both AApoAII and AA amyloidosis could be induced in this system, but the two types of amyloid fibrils preferentially promote the formation of the same type of fibrils while inhibiting the formation of the other. Furthermore, we demonstrate that AA or AApoAII amyloidosis could be cross-seeded by predeposited AApoAII or AA fibrils and that the predeposited amyloid fibrils were degraded when the fibril formation was reduced or stopped. In addition, a large proportion of the two amyloid fibrils colocalized during the formation of new fibrils in the spleen and liver. Thus, we propose that AApoAII and AA can both cross-seed and cross-compete with regard to amyloid formation, depending on the stage of amyloidogenesis. These results will aid in the clarification of the mechanisms of pathogenesis and progression of amyloid disorders.

AA amyloidosis-resistant CE/J mice haveSaa1andSaa2genes that encode an identical SAA isoform

“…Furthermore, it has been shown that AA can cross-seed and cross-compete with other amyloid fibrils, such as that observed for the AApoAII in an induced amyloidosis mouse model [8].…”

Amyloid fibrils: potential food safety implications

“…Though amyloid fibril formation may be a generic property of polypeptide chains (Dobson, 1999), in vivo, only 26 different proteins are known to form fibrils naturally (Yan et al, 2007). Since amyloidoses are classified by the amassing protein, 26 different types of amyloidosis have been described.…”

“…While the build-up of Islet Amyloid Polypeptide (IAPP) in insulin-secreting cells is a hallmark of a substantial proportion of T2D (Hull et al, 2004), the role amyloid IAPP plays in the disease remains unclear. Some 'consider T2D to be a form of islet Alzheimer disease' (Prentki and Nolan, 2006) and even suggest that one of the reasons diabetics have higher rates of Alzheimer's is that pancreatic amyloid fibrils may be cross-seeding amyloid-in their own brains (Yan et al, 2007), though IAPP fails to seed the formation of A (1-40) fibrils in vitro (O'Nuallain et al, 2004). Amyloid deposits (including A and AA) have also been found in arterial atherosclerotic plaques, but the role they play, if any, is likewise unknown (Howlett and Moore, 2006), hindering efforts to understanding the extent of the potential risk associated with dietary amyloid exposure.…”

“…These fibrils tend to accumulate extracellularly, generating amyloid deposits that may disrupt tissue structure and function. PrP C is but 1 of 26 different precursor proteins known capable of forming amyloid in vivo (Yan et al, 2007). There is growing evidence that amyloid fibrils other than prions may be a potential source of foodborne contagion as well.…”

C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice

“…These samples were examined under an electron microscope (1200EX or 1400EX; JEOL) with an acceleration voltage of 80 kV. Immunoelectron microscopy was performed using a modified method in parts described previously (51). The preincubated seeds with biotin-labeled a48/65 (N62K) were resuspended in the reaction solution and recentrifuged.…”