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Abstract
Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of β2-microglobulin (β2m) into amyloid fibrils (Aβ2M). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie Aβ2M fibril formation in DRA, we generated transgenic mice that overexpress human β2m protein in a mouse β2m gene knockout background (hB2MTg+/+ mB2m+/+). The hB2MTg+/+mB2m−/− mice express a high level of human β2m protein in many tissues as well as a high plasma β2m concentration (192.8 mg/L). This concentration is >100 times higher than that observed in healthy humans and >4 times higher than that detected in patients on dialysis. We examined spontaneous and amyloid fibril-induced amyloid deposition in these mice. Amyloid deposition of β2m protein was not observed in aged or amyloid fibril injected animals. However, mouse senile apolipoprotein A-II amyloidosis (AApoAII) was detected, particularly in the joints of mice that were injected with AApoAII amyloid fibrils.
This study demonstrates that this mouse model could be valuable in studying the components and conditions that promote DRA, and indicates that high plasma concentrations of hβ2m as well as seeding with pre-existing amyloid fibrils may not be sufficient to induce Aβ2M.
| Abbreviations | ||
| AI | = | amyloid index |
| apoA-II | = | apolipoprotein A-II |
| DRA | = | dialysis-related amyloidosis |
| ß2m | = | ß2-microglobulin |
| CMV-IE | = | cytomegalovirus immediate early gene enhancer |
| PAGE | = | polyacrylamide gel electrophoresis |
| PBS | = | phosphate buffered saline |
| PVDF | = | polyvinylidene difluoride |
| RT-PCR | = | reverse transcription polymerase chain reaction |
| SPF | = | specific pathogen free |
| ThT | = | thioflavin T |
| TTR | = | transthyretin |
| Abbreviations | ||
| AI | = | amyloid index |
| apoA-II | = | apolipoprotein A-II |
| DRA | = | dialysis-related amyloidosis |
| ß2m | = | ß2-microglobulin |
| CMV-IE | = | cytomegalovirus immediate early gene enhancer |
| PAGE | = | polyacrylamide gel electrophoresis |
| PBS | = | phosphate buffered saline |
| PVDF | = | polyvinylidene difluoride |
| RT-PCR | = | reverse transcription polymerase chain reaction |
| SPF | = | specific pathogen free |
| ThT | = | thioflavin T |
| TTR | = | transthyretin |
Acknowledgements
This work was supported by grants for the Amyloidosis Research Committee from the Ministry of Health, Labor and Welfare, Japan.