Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients.

Abstract

Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 microM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Abeta concentrations showed a significant (p < 0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p< 0.05). Our results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that lovastatin reduces Abeta formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.

• Authors: Joseph D Buxbaum, Edward I Cullen, Lawrence T Friedhoff
• Journal: Frontiers in bioscience : a journal and virtual library (Front Biosci) Vol. 7 Pg. a50-9 (Apr 01 2002) ISSN: 1093-9946 [Print] United States
• PMID: 11900994 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Peptide Fragments
• Cholesterol
• Lovastatin

Topics

• Adult
• Aged
• Alzheimer Disease (etiology)
• Amyloid beta-Peptides (blood, metabolism)
• Animals
• CHO Cells
• Cell Line
• Cholesterol (metabolism)
• Cricetinae
• Dogs
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hypercholesterolemia (blood, complications, drug therapy)
• Lovastatin (pharmacology)
• Male
• Middle Aged
• Peptide Fragments (blood, metabolism)