Inhaltszusammenfassung

Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (A beta PP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We dem...Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (A beta PP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human neuroblastoma cells with 50 mu M zaragozic acid resulted in a similar to 3 fold increase of alpha-secretase activity and reduced cellular cholesterol by similar to 30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 mu M). Zaragozic acid-stimulated secretion of alpha-secretase cleaved soluble A beta PP was dose dependent and saturable. Lovastatin-or zaragozic acid-stimulated increase of alpha-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the alpha-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave A beta PP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for alpha-secretase activation.» weiterlesen» einklappen

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DDC Sachgruppe:
Medizin