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Published on: March 16, 2016
Mouse model to study human A beta2M amyloidosis: generation of a transgenic mouse with excessive expression of human
Pengyao Zhang1, Xiaoying Fu, Jinko Sawashita
1Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.
Abstract:
Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of beta(2)-microglobulin (beta(2)m) into amyloid fibrils (Abeta(2)M). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie Abeta(2)M fibril formation in DRA, we generated transgenic mice that overexpress human beta(2)m protein in a mouse beta(2)m gene knockout background (hB2MTg(+/+) 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 hbeta(2)m as well as seeding with pre-existing amyloid fibrils may not be sufficient to induce Abeta(2)M.
Insights
Dialysis-related amyloidosis (DRA) involves beta(2)-microglobulin (beta(2)m) deposition. This study found that high beta(2)m levels and amyloid seeding were insufficient to induce Abeta(2)M in a new mouse model.
Area of Science:
- Biochemistry
- Nephrology
- Genetics
Background:
- Dialysis-related amyloidosis (DRA) is a complication of long-term hemodialysis.
- Beta(2)-microglobulin (beta(2)m) deposition forms amyloid fibrils (Abeta(2)M) in DRA.
- The exact pathogenesis of amyloid deposition in DRA remains unclear.
Purpose of the Study:
- To investigate the mechanisms of Abeta(2)M fibril formation in DRA.
- To develop and utilize a transgenic mouse model for studying DRA pathogenesis.
Main Methods:
- Generated transgenic mice overexpressing human beta(2)m in a beta(2)m knockout background.
- Achieved high plasma beta(2)m concentrations in the mice (>100x healthy humans).
- Examined spontaneous and induced amyloid deposition, including seeding with amyloid fibrils.
Main Results:
- Transgenic mice exhibited high plasma beta(2)m levels but did not develop Abeta(2)M.
- No beta(2)m amyloid deposition was observed in aged or amyloid fibril-injected mice.
- Mouse senile apolipoprotein A-II amyloidosis (AApoAII) was detected in some mice.
Conclusions:
- The developed mouse model is potentially valuable for studying DRA.
- High plasma beta(2)m concentrations alone are insufficient to induce Abeta(2)M.
- Amyloid seeding with pre-existing fibrils may also not be sufficient for Abeta(2)M formation in this model.
