Clarification of the molecular pathogenesis of human amyloidosis by in vitro amyloid fibril formation systems and transgenic mouse model

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In order to clarify the molecular pathogenesis of amyloidoses including dialysis -related amyloidosis orβ2-microglobulin (β2-m) amyloidosis, we constructed experimental amyloid fibril formation systems in vivo and in vitro, and then evaluated the roles of the various biological molecules on the amyloid fibril formation. The key findings of this study are as follows: (1) The detailed molecular mechanism of α2-macroglobulin as an extracellular molecular chaperon in the inhibition of β2-microglobulin amyloid fibril formation was clarified. (2) Human β2-m transgenic mice expressing excess amount of β2-m did not showed the amyloid symptom, indicating unknown intrinsic factors are required for the deposition of amyloid fibril in vivo. (3) Toxic effect of the β2-m amyloid fibril on the cultured synovial fibroblast cells was evaluated. (4) We improved the in vitro fibril formation system to investigate the effect of various biological molecules and organic compounds on the fibrillogenesis at near physiological conditions.