Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation.
Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.
Schwarzman
A L
AL
Department of Psychiatry, School of Medicine, State University of New York at Stony Brook 11794-8101, USA.
Goldgaber
D
D
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000209:etiology / Q000378:metabolism*; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism*; D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D011228:Prealbumin / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding
D000682:Amyloid; D016229:Amyloid beta-Peptides; D011228:Prealbumin; C076571:transthyretin-related amyloid fibril protein, human