Processing of Amyloid Precursor Protein as a Biochemical Link Between Atherosclerosis and Alzheimers Disease

D.   M.   Jans; W.      Martinet; T.   J.L.   Van De Parre; A.   G.   Herman; H.      Bult; M.   M.   Kockx; G.   R.Y.   De Meyer

Abstract

Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid β (Aβ ), a peptide extensively studied in Alzheimers disease and that is cleaved from APP by β - and γ-secretase, and/or Aβ-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Aβ -like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMGCoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Aβ formation in Alzheimers disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter -secretase activity in Alzheimers disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of A -containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimers disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.

Keywords: Atherosclerosis, Alzheimer's disease, amyloid precursor protein, β-amyloid peptide, platelet phagocytosis, macrophage activation, inducible nitric oxide synthase, non-steroidal anti-inflammatory drugs, statins