Mouse model to study human A β₂M amyloidosis: generation of a transgenic mouse with excessive expression of human β₂-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.

C. elegans Expressing Human β2-Microglobulin: A Novel Model for Studying the Relationship between the Molecular Assembly and the Toxic Phenotype

“…In vivo models of systemic amyloidosis are urgently needed and this is particularly required for β 2 -m associated disease where any attempt to generate an animal model to recapitulate the key molecular aspects of the pathology have currently failed [10]. β 2 -m is the non-covalently bound light chain of the major histocompatibility complex class I (MHCI).…”

The Extracellular Chaperone Haptoglobin Prevents Serum Fatty Acid-promoted Amyloid Fibril Formation of β2-Microglobulin, Resistance to Lysosomal Degradation, and Cytotoxicity

“…Eventually, fibrillar deposition of ␤2m occurs in the joints of patients undergoing dialysis for extended periods of time and leads to acute inflammation and tissue destruction by infiltrating macrophages, a pathological condition termed dialysis-related amyloidosis (4). Interestingly, amyloid fibril deposition did not occur in transgenic mice expressing elevated levels of human ␤2m either alone or when injected with the fibril seed (5). A critical balance of hydrophobic and hydrophilic interactions as modulated by environmental factors, for example anionic cosolutes, is important for the amyloid fibril formation of ␤2m (6).…”

Beta-2 Microglobulin Amyloidosis: Past, Present, and Future

“…Conversely, Zhang rendered a different conclusion regarding the role of high B2M levels in amyloidogenesis. In an animal model, employing B2M concentrations at 4-fold higher concentrations than in plasma from HD patients, spontaneous fibrillogenesis failed to occur, implying that elevated B2M concentrations alone were insufficient to produce amyloid 30 . A separate observation in which a mutant thermodynamically unstable B2M variant produced amyloid at normal serum levels of B2M 31 lent further credence to the notion that other permissive factors of fibrillogenesis, aside from elevated B2M concentrations, were required.…”