α2-Macroglobulin (α2M) is an abundant plasma/extracellular space protein implicated in clearance of amyloid β (Aβ), a key constituent of Alzheimer's disease (AD) plaques. α2M 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 α2M function. In this study, we examined the subunit and conformational structure of α2M in AD plasma samples, and its capacity to bind trypsin, transforming growth factor-β1, and Aβ. Plasma from patients homozygous for the deletion (DD) showed normal α2M subunit size, conformation, and proteinase inhibitory activity. Interestingly, plasma α2M from two DD patients showed markedly increased TGF-β1 binding. Moreover, methylamine-treated DD plasma samples showed modest, but significant, elevations in Aβ binding to α2M* 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.
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