Functional analysis of plasma alpha(2)-macroglobulin from Alzheimer's disease patients with the A2M intronic deletion
Caroline Hope1, Joseph Mettenburg, Steven L Gonias
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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.
Insights
A genetic deletion in the A2M gene may impact Alzheimer's disease (AD) pathogenesis by altering alpha(2)-macroglobulin (alpha(2)M) binding of amyloid beta. This study found altered binding in patients with the deletion.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alpha-2-macroglobulin (alpha(2)M) is crucial for clearing amyloid beta (Abeta), a key component of Alzheimer's disease (AD) plaques.
- Genetic studies have debated the role of an A2M gene deletion in late-onset AD, but its functional impact remains unclear.
Purpose of the Study:
- To investigate the functional consequences of the A2M gene deletion on alpha(2)M structure and function in AD patients.
- To assess alpha(2)M's binding capacity for trypsin, transforming growth factor-beta1 (TGF-beta1), and Abeta in individuals with and without the A2M deletion.
Main Methods:
- Analysis of alpha(2)M subunit size and conformation in plasma from AD patients homozygous for the A2M deletion (DD) and controls.
- Assay of alpha(2)M's binding activity for trypsin, TGF-beta1, and Abeta using plasma samples.
Main Results:
- Plasma alpha(2)M from DD patients exhibited normal subunit size, conformation, and proteinase inhibitory activity.
- Markedly increased TGF-beta1 binding was observed in alpha(2)M from two DD patients.
- Methylamine-treated plasma from DD patients showed significantly elevated Abeta binding to alpha(2)M compared to controls.
Conclusions:
- The A2M deletion may influence AD pathogenesis through altered alpha(2)M binding of TGF-beta1 and Abeta.
- These findings suggest a potential functional mechanism linking the A2M deletion to multifactorial AD development.
