Animal models for reactive amyloidosis.
For over 70 years animal experiments have been performed to elucidate the pathogenesis of reactive amyloidosis and to investigate the formation of the beta-pleated sheet-rich amyloid fibrils in general. In appropriate species, primarily rodents like mouse and hamster, amyloid is formed after stimulation with amyloid-inducing injections after a lag phase (secondary or reactive amyloid, AA amyloid). For the formation of this AA amyloid, elevated values in blood of its precursor protein, SAA, is the first prerequisite. SAA is an acute phase protein of hepatic origin, released after stimulation by cytokines, and is associated in serum with high-density lipoprotein (apoSAA). In mouse, hamster and mink amyloidogenic subtypes of SAA are found. In the rat SAA is absent, although its mRNA is transcribed. Evidence is increasing that SAA crystallizes to fibrils first, whilst loss of its C-terminal end can be a post-fibrillogenic phenomenon. Glycoproteins, proteoglycans, glycosaminoglycans and lipids are reintroduced in experimental amyloid research. Basement membrane heparan sulphate proteoglycans (perlecans) are attributed to have a primary role. The pentraxin serum amyloid P-component is a calcium-dependent secondary phenomenon. Membrane-bound, lipid-rich vesicles are found amongst the newly deposited pericellular amyloid fibrils. These vesicles probably have to be interpreted as indicators of primary membrane alteration during amyloid fibril crystallization. The vesicles will be formed after rupture of the membranes caused by the stiff intramembranously crystallized protein fibrils. Morphological evidence supporting this hypothesis has been found in immunoelectron microscopical studies. Accumulation of intramembranous SAA preceded amyloid fibril deposition. Fibril formation then might be related to conformational change of the intramembranous SAA. The lag phase for amyloid deposition is shortened after a single injection of a fraction of amyloid, the AEF. It is a low-molecular-weight glycoprotein that easily associates with other molecules. When isolated from amyloid fibrils, the (F)AEF contains a large proportion of beta-pleated sheet molecular structure. It is probable that this structure holds an explanation for its enhancing potency: forming a nidus for physical crystallization. The major substances and animal species used in animal experiments on amyloidosis, are mentioned. Overlooked by-effects of amyloidogenic stimuli are discussed. Polyarthritis after systemic endotoxin injections found in the hamster acts as a source of cytokines, further triggering the reactive amyloidosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
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D000686:Amyloidosis / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D000685:Serum Amyloid A Protein / Q000378:metabolism
D000685:Serum Amyloid A Protein