Journal
AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS
Volume 17, Issue 2, Pages 50-62Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/13506129.2010.483116
Keywords
Amyloid deposition; beta(2)-microglobulin; dialysis-related amyloidosis; knockout mouse; transgenic mouse
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Funding
- Ministry of Health, Labor and Welfare, Japan
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Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of beta(2)-microglobulin (beta(2)m) into amyloid fibrils (A beta M-2). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie A beta M-2 fibril formation in DRA, we generated transgenic mice that overexpress human beta(2)m protein in a mouse beta(2)m gene knockout background (h beta(2)MTg(+/+) mB2m(+/+)). The hB2MTg(+/+)mB2m(-/-) mice express a high level of human beta(2)m protein in many tissues as well as a high plasma beta(2)m 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 beta(2)m 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 h beta(2)m as well as seeding with pre-existing amyloid fibrils may not be sufficient to induce A beta M-2.
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