title: Mouse model to study human A beta2M amyloidosis: generation of a transgenic mouse with excessive expression of human beta2-microglobulin.
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.
authors.affiliation: Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Pengyao
authors.initials: P
authors.lastname: Zhang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Fu
authors.forename: Jinko
authors.initials: J
authors.lastname: Sawashita
authors.forename: Junjie
authors.initials: J
authors.lastname: Yao
authors.forename: Beiru
authors.initials: B
authors.lastname: Zhang
authors.forename: Jinze
authors.initials: J
authors.lastname: Qian
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomozawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Hironobu
authors.initials: H
authors.lastname: Naiki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Higuchi
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D001613:beta 2-Microglobulin / Q000097:blood / Q000235:genetics* / Q000652:urine
chemical_list: D000682:Amyloid; D016633:Apolipoprotein A-II; D001613:beta 2-Microglobulin