Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants

Abstract

Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy. However, though an amyloidogenic protein itself, TTR inhibits aggregation of Alzheimer's amyloid beta protein (Aβ) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations influence the ability of TTR to inhibit Aβ amyloidosis, forty-seven recombinant TTR variants were produced and analyzed. We showed that all recombinant proteins formed tetramers and were functional in thyroxine binding. Acid denaturation at pH 3.8 resulted in aggregation and fibril formation of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH 6.8. Most TTR variants bound to Aβ and inhibited Aβ aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to Aβ and decreased inhibition of Aβ aggregation. Only TTR G42 and TTR P55 completely failed to bind Aβ and to inhibit Aβ aggregation. We suggest that TTR variants characterized by decreased binding to Aβ or by decreased inhibition of Aβ aggregation in vitro may contribute to Aβ amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.