Haptoglobin Interacts with Apolipoprotein E and Beta-Amyloid and Influences Their Crosstalk

• Published in: ACS chemical neuroscience 2014-09, Vol.5 (9), p.837-847
• Main Authors: Spagnuolo, Maria Stefania, Maresca, Bernardetta, La Marca, Valeria, Carrizzo, Albino, Veronesi, Carlo, Cupidi, Chiara, Piccoli, Tommaso, Maletta, Raffaele Giovanni, Bruni, Amalia Cecilia, Abrescia, Paolo, Cigliano, Luisa
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - pathology; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Analysis of Variance; Animals; Apolipoproteins E - metabolism; Brain - metabolism; CHO Cells; Cricetulus; Enzyme-Linked Immunosorbent Assay; Female; Haptoglobins - genetics; Haptoglobins - metabolism; Humans; Immunoprecipitation; Male; Middle Aged; Mutation - genetics; Protein Binding - drug effects; Protein Binding - physiology; Transfection
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/cn500099f

Beta-amyloid accumulation in brain is a driving force for Alzheimer’s disease pathogenesis. Apolipoprotein E (ApoE) represents a critical player in beta-amyloid homeostasis, but its role in disease progression is controversial. We previously reported that the acute-phase protein haptoglobin binds ApoE and impairs its function in cholesterol homeostasis. The major aims of this study were to characterize the binding of haptoglobin to beta-amyloid, and to evaluate whether haptoglobin affects ApoE binding to beta-amyloid. Haptoglobin is here reported to form a complex with beta-amyloid as shown by immunoblotting experiments with purified proteins, or by its immunoprecipitation in brain tissues from patients with Alzheimer’s disease. The interaction between ApoE and beta-amyloid was previously shown to be crucial for limiting beta-amyloid neurotoxicity and for promoting its clearance. We demonstrate that haptoglobin, rather than impairing ApoE binding to beta-amyloid, promotes to a different extent the formation of the complex between beta-amyloid and ApoE2 or ApoE3 or ApoE4. Our data suggest that haptoglobin and ApoE functions in brain should be evaluated taking into account their mutual interaction with beta-amyloid. Hence, the risk of developing Alzheimer’s disease might not only be linked to the different ApoE isoforms, but also rely on the level of critical ligands, such as haptoglobin.