N-truncation and pyroglutaminylation enhances the opsonizing capacity of Aβ-peptides and facilitates phagocytosis by macrophages and microglia.

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.