Anti-amyloidogenic properties of recombinant transthyretin variants

 

Schwarzman, A.^1,2, Runova, O ²., Solovyev ² K, Sarantseva, S.¹ , Vitek, M³.

¹ Petersburg Institute of Nuclear Physics Russian Academy of Sciences, St. Petersburg, Gatchina, Russia² Institute for Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg, Russia³ Cognosci Inc., Research Triangle Park, North Carolina, USA

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 (Ab) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations infuence the ability of TTR to inhibit Ab amyloidosis, forty-seven recombinant TTR variants were produced. Most TTR variants bound to Ab and inhibited Ab aggregation in vitro. TTR variants S64, A71, Q89, H114 and I122 revealed decreased binding to Ab and decreased inhibition of Ab aggregation. Only TTR G42 and TTR P55 completely failed to bind Ab and to inhibit Ab aggregation. We suggest that TTR variants with decreased binding to Ab and decreased inhibition of Ab aggregation may contribute to Ab amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.