Amyloidosis and female protein in the Syrian hamster. Concurrent regulation by sex hormones.

Abstract

Previous results have shown that when compared to male Syrian hamsters, female Syrian hamsters have a distinct predisposition to acquire amyloidosis either normally with aging or experimentally with sodium caseinate or diethylstilbestrol (DES) treatments. In the present study, we tested the influence of testosterone on expression of amyloid to determine if this hormone was solely responsible for the sex-limited amyloidosis of the Syrian hamster. Males deprived of testosterone by castration acquired amyloid at an unusually young age, an age of onset similar to that in female hamsters. Also, the amyloidogenic effect of DES in male Syrian hamsters was inhibited by concomitant injections of testosterone, indicating that estrogens induce amyloid in male hamsters by inhibiting testosterone synthesis. When administered to female hamsters, testosterone inhibited expression of amyloid in aging female Syrian hamsters and extended the life span of this gender. Of the two components of amyloid, the major component Amyloid A-derived fibril or the minor constituent, Amyloid P component, only the P component is under sex hormone control in the Syrian hamster; testosterone inhibits the hepatic synthesis of the P component homologue (called female protein), which is normally expressed 100-200-fold greater in female vs. male Syrian hamster. In general, the serum level of female protein under various experimental conditions correlated with the presence of amyloid and indicated that in the Syrian hamster the P component homologue is of primary importance in the deposition of amyloid.

Transgenic Mouse Model of AA Amyloidosis

“…Notably, in addition to the renal tubular casts, plasma cell infiltrates in spleen and lymph nodes, and manifestations of myelocytic and megakaryocytic hyperplasia, mice now have AA-related amyloid deposits in the spleen, liver, and kidneys. We have found that amyloid deposition can be detected as early as ϳ3 months of age, progresses over time, and, as is the case with hamsters that develop AA amyloid as a consequence of aging, 28 is more pronounced in females for unknown reasons. Further, mice carrying the hIL6 gene are heterozygotes and attempts to create a homozygote have been unsuccessful, presumably due to prenatal lethality.…”

The pentraxins, C-reactive protein and serum amyloid P component, are cleared and catabolized by hepatocytes in vivo.

“…For example, firstly, the rapid production and clearance of CRP have made it the marker of choice for monitoring of the acute phase response and it is widely used in clinical practice for determining the presence, extent, and activity of many infective and inflammatory disorders (6). Secondly, several lines of evidence suggest that SAP may participate in the persistence of amyloid deposits in vivo: SAP levels correlate with amyloidogenesis in experimental animal models (7)(8)(9), SAP is inherently proteinase resistant (10), and SAP in human amyloid deposits in vivo is neither degraded ( 11 ) nor modified (3 ). The route of catabolism of SAP may thus be important in amyloidogenesis.…”

Comparative analyses of pentraxins: implications for protomer assembly and ligand binding

“…On the other hand, human SAP specifically binds to the 4,6 cyclic pyruvate acetal of [3-D-galactose (MO3DG) [16] and also to all types of amyloid fibrils [17], which are not recognized by human CRP. The major pentraxin in Syrian hamsters, formerly known as female protein [18] (here designated HSAP), is the hamster counterpart of human SAP, in that it binds to hamster amyloid [19,20], but it shares with human CRP the capacity to bind to PC as well as PE [18,21].…”