title: Functional analysis of plasma alpha(2)-macroglobulin from Alzheimer's disease patients with the A2M intronic deletion.
abstract: alpha(2)-Macroglobulin (alpha(2)M) is an abundant plasma/extracellular space protein implicated in clearance of amyloid beta (Abeta), a key constituent of Alzheimer's disease (AD) plaques. alpha(2)M also regulates proteinase and growth factor activities. In recent years, there have been >30 genetic studies debating the controversial role of a five-base-pair intronic deletion in the A2M gene in late-onset AD. However, little is known about potential effects of the deletion upon alpha(2)M function. In this study, we examined the subunit and conformational structure of alpha(2)M in AD plasma samples, and its capacity to bind trypsin, transforming growth factor-beta1, and Abeta. Plasma from patients homozygous for the deletion (DD) showed normal alpha(2)M subunit size, conformation, and proteinase inhibitory activity. Interestingly, plasma alpha(2)M from two DD patients showed markedly increased TGF-beta1 binding. Moreover, methylamine-treated DD plasma samples showed modest, but significant, elevations in Abeta binding to alpha(2)M* compared with samples from patients lacking the deletion. These observations suggest a possible functional basis by which the A2M deletion may influence multifactorial AD pathogenesis.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hope
authors.forename: Joseph
authors.initials: J
authors.lastname: Mettenburg
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D011869:Radioligand Assay; D017384:Sequence Deletion; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014357:Trypsin / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000511:alpha-Macroglobulins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001798:Blood Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000511:alpha-Macroglobulins; D014357:Trypsin