Effect of Non-Steroidal Anti-Inflammatory Drugs on Amyloid-β Formation and Macrophage Activation after Platelet Phagocytosis

Abstract

Recently, we showed that platelet phagocytosis occurs in human atherosclerotic plaques and leads to foam cell formation. Platelet phagocytosis, resulting in macrophage activation and iNOS induction, was associated with the formation of amyloid-beta peptide (Abeta) via proteolytic cleavage of platelet-derived amyloid precursor protein (APP), possibly by secretases. To test the involvement of gamma-secretase in this process, we used indomethacin, ibuprofen, and sulindac sulfide, non-steroidal anti-inflammatory drugs (NSAIDs) known to alter the gamma-secretase cleaving site of APP, on their ability to inhibit macrophage activation evoked by platelet phagocytosis. J774 macrophages were incubated with human platelets or lipopolysaccharide (LPS) with or without NSAIDs. Nitrite was quantified as a measure for inducible nitric oxide synthase (iNOS) activity. Indomethacin, ibuprofen, sulindac sulfide, and meloxicam concentration-dependently reduced nitrite production by macrophages incubated with platelets, but did not alter LPS-induced iNOS activity or platelet uptake. However, acetylsalicylic acid and naproxen, two NSAIDs without effect on the gamma-secretase cleaving site of APP, did not affect nitrite production in either platelet- or LPS-stimulated macrophages. Surface-enhanced laser desorption/ionization time-of-flight mass-spectrometry demonstrated time-dependent formation of Abeta-containing peptides after platelet phagocytosis, which could be inhibited by indomethacin. In conclusion, these results point to the involvement of gamma-secretase in macrophage activation following platelet phagocytosis.

Platelets modulate atherogenesis and progression of atherosclerotic plaques via interaction with progenitor and dendritic cells

“…Only recently, Jans et al. showed that platelet phagocytosis by macrophages occurs in atherosclerotic plaques and results in foam cell formation involving amyloid β‐peptide [80]. Intriguingly, in our investigations we were able to show that dendritic cells also substantially internalize platelets, when coincubated over several days [81] (Fig.…”

Untangling the role of amyloid in atherosclerosis

“…Immunohistochemical analysis of human atherosclerotic lesions identified b-amyloid peptides in activated perivascular macrophages that had phagocytosed platelets, supporting the notion that this mechanism promotes b-amyloid accumulation in vivo. Furthermore, a subset of nonsteroidal anti-inflammatory drugs that affect APP processing by g-secretase and b-amyloid generation in Alzheimer's disease also reduces macrophage activation after platelet phagocytosis and inhibits the formation of b-amyloid peptide [27]. Together, these data support a role for platelet-macrophage interactions in the generation of b-amyloid peptide in atheroma.…”

Aspirin regulates expression and function of scavenger receptor‐BI in macrophages: studies in primary human macrophages and in mice

“…To strengthen this view and to clarify whether the observed effects were inherent to aspirin and sodium salicylate, cells were incubated with two well-known COX1/2 inhibitors, ibuprofen and naproxen. Corresponding to previous reports, we used increasing concentrations of ibuprofen and naproxen up to 100 mol/l and 300 mol/l, respectively (21)(22)(23). Neither compound was shown to influence SR-BI expression (Fig.…”