Cholesterol and Alzheimer's disease.
Accumulation of a 40-42-amino acid peptide, termed amyloid-beta peptide (A beta), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit A beta could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit A beta production. Increasing evidence suggests that the enzymes that generate A beta function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit A beta production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-beta-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases A beta production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce A beta levels in blood of patients by up to 40%. The putative role of A beta in AD raises the possibility that treating patients with statins might lower A beta, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce A beta offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.
Department of Pharmacology, Loyola University Medical Center, Bldg. 102, Rm. 3634, 2160 South First Avenue, Maywood, IL 60153, USA. bwolozi@lumc.edu.
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Wolozin
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D016282:Aspartic Acid Endopeptidases; D002784:Cholesterol / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use
D016564:Amyloid beta-Protein Precursor; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human