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

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 beta (Abeta), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by beta- and gamma-secretase, and/or Abeta-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 Abeta-like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Abeta formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter gamma-secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of Abeta-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 Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.

Transcription Profiles of Aortic Smooth Muscle Cells from Atherosclerosis-Prone and -Resistant Regions in Young Apolipoprotein E-Deficient Mice before Plaque Development

“…Moreover, during platelet phagocytosis, macrophages become activated, as indicated by the upregulation of proinflammatory genes, such as inducible nitric oxide synthase. App was essential for the activation of macrophages, since blood platelets of App-deficient mice were phagocytosed, but failed to activate macrophages [57]. The present study shows that App is expressed at a higher level in SMCs in the atherosclerosis-prone AA of apoE–/– mice, and this warrants further study of its role in atherogenesis.…”

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

“…This domain has an important role in the coagulation cascade where it functions as an inhibitor of factors, IXa, Xa, XIa and tissue factor VIIa complex [52]. AβPP and Aβ peptides have been observed in atherosclerotic plaque macrophages that have engulfed platelets in areas of neo-vascularization [53;54]. Although platelets and circulating Aβ may be a significant source of these peptides in the atherosclerotic lesions, it is possible that additional Aβ peptides originate directly from the arterial tunica media myocytes and endothelial cells that also express the AβPP molecule [55].…”

Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability

“…3). Because uptake of platelets from APP knockout mice by macrophages does not result in macrophage activation [75], APP or derived fragments can be considered the effector molecules that induce macrophage activation after platelet phagocytosis. Interestingly, macrophage activation after platelet phagocytosis is increased in the presence of thrombin, which is a substance that evokes platelet degranulation.…”