Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants.
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 (A beta) 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 A beta 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 A beta and inhibited A beta aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to A beta and decreased inhibition of A beta aggregation. Only TTR G42 and TTR P55 completely failed to bind A beta and to inhibit A beta aggregation. We suggest that TTR variants characterized by decreased binding to A beta or by decreased inhibition of A beta aggregation in vitro may contribute to A beta amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.
Schwarzman
Alexander L
AL
Department of Psychiatry and Behavioral Science, SUNY at Stony Brook, Stony Brook, New York 11794, USA.
Tsiper
Maria
M
Wente
Henning
H
Wang
Audrey
A
Vitek
Michael P
MP
Vasiliev
V
V
Goldgaber
Dmitry
D
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D011228:Prealbumin; D011994:Recombinant Proteins