title: N-truncation and pyroglutaminylation enhances the opsonizing capacity of Aβ-peptides and facilitates phagocytosis by macrophages and microglia.
abstract: Abnormal accumulations of amyloid-β (Aβ)-peptides are one of the pathological hallmarks of Alzheimer's disease (AD). The precursor of the Aβ-peptides, the amyloid precursor protein (APP), is also found in peripheral blood cells, but its function in these cells remains elusive. We previously observed that mononuclear phagocytes release Aβ-peptides during activation and phagocytosis, suggesting a physiologic role in inflammatory processes. Here, we show that supplementing the media with soluble N-terminally truncated Aβ(2-40) and Aβ(2-42) as well as Aβ(1-42) induced the phagocytosis of polystyrene particles (PSPs) by primary human monocytes. If the PSPs were pre-incubated with Aβ-peptides, phagocytosis was induced by all tested Aβ-peptide species. N-terminally truncated Aβ(x-42) induced the phagocytosis of PSPs significantly more effectively than did Aβ(x-40). Similarly, the phagocytosis of Escherichia coli by GM-CSF- and M-CSF-elicited macrophages as well as microglia was particularly facilitated by pre-incubation with N-terminally truncated Aβ(x-42). The proinflammatory polarization of monocytes was indicated by the reduced MSRI expression and IL-10 secretion after phagocytosis of PSPs coated with Aβ(1-42), Aβ(2-42) and Aβ(3p-42). Polarization of the macrophages by GM-CSF reduced the phagocytic activity, but it did not affect the capabilities of Aβ-peptides to opsonize prey. Taken together, Aβ-peptides support phagocytosis as soluble factors and act as opsonins. Differential effects among the Aβ-peptide variants point to distinct mechanisms of interaction among monocytes/macrophages, prey and Aβ-peptides. A proinflammatory polarization induced by the phagocytosis of Aβ-peptide coated particles may provide a model for the chronic inflammatory reaction and sustained plaque deposition in AD.
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Mateja
authors.initials: M
authors.lastname: Condic
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Timo Jan
authors.initials: TJ
authors.lastname: Oberstein
authors.affiliation: Department of Medicine III, Institute for Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg, Gluecksstraße 4a, D-91054 Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Mareike Carola
authors.initials: MC
authors.lastname: Reimann
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Maler
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. Electronic address: Philipp.Spitzer@uk-erlangen.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Spitzer
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D004926:Escherichia coli; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D017628:Microglia / Q000502:physiology*; D008863:Microspheres; D009000:Monocytes / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009895:Opsonin Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010587:Phagocytosis; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D013329:Structure-Activity Relationship; D034421:Sus scrofa; D013552:Swine
chemical_list: D016229:Amyloid beta-Peptides; C508609:IL10 protein, human; D009895:Opsonin Proteins; D010446:Peptide Fragments; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D011761:Pyrrolidonecarboxylic Acid
keywords: Amyloid precursor protein; Aβ-peptides; Macrophage; Macrophage polarization; Monocyte; Neuroinflammation; Opsonization; Phagocytosis