Functional analysis of plasma α2-macroglobulin from Alzheimer's disease patients with the A2M intronic deletion

Caroline Hope; Joseph Mettenburg; Steven L Gonias; Steven T DeKosky; M.Ilyas Kamboh; Charleen T Chu

Neurobiology of Disease (Dec 2003)

Functional analysis of plasma α2-macroglobulin from Alzheimer's disease patients with the A2M intronic deletion

Caroline Hope,
Joseph Mettenburg,
Steven L Gonias,
Steven T DeKosky,
M.Ilyas Kamboh,
Charleen T Chu

Affiliations

Caroline Hope: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
Joseph Mettenburg: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
Steven L Gonias: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
Steven T DeKosky: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
M.Ilyas Kamboh: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
Charleen T Chu: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA

Journal volume & issue: Vol. 14, no. 3
pp. 504 – 512

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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