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From the Department of Neurology, University of Tübingen (Drs. Simons, Dichgans, and Schulz), and Max Planck Institute of Molecular Cell Biology and Genetics, Dresden (Dr. Keller), Germany.
Address correspondence and reprint requests to Dr. M. Simons, Department of Neurology, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany; e-mail: mika_simons{at}hotmail.com
Article abstract—— The Aß-amyloid peptide (Aß), the main component of amyloid plaques, is derived by proteolytic cleavage from the amyloid precursor protein (APP). Epidemiologic and biochemical data suggest a link between cholesterol, APP processing, Aß, and Alzheimer’s disease. Two recent epidemiologic studies indicate that there is a decreased prevalence of AD associated with the use of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase inhibitors or statins). Experiments in cell culture and in vivo demonstrate that treatment with statins reduces production of Aß. The authors discuss how cholesterol might modulate Aß deposit formation. As neurons receive only small amounts of exogenous cholesterol, statins that efficiently cross the blood–brain barrier may reduce the amount of neuronal cholesterol below a critical level. Decreased neuronal cholesterol levels inhibit the Aß-forming amyloidogenic pathway possibly by removing APP from cholesterol- and sphingolipid-enriched membrane microdomains. In addition, depletion of cellular cholesterol levels reduces the ability of Aß to act as a seed for further fibril formation. These intriguing relationships raise the hopes that cholesterol-lowering strategies may influence the progression of AD.
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