IMR Press / FBL / Volume 7 / Issue 1 / DOI: 10.2741/A739

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article

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

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1 Laboratory of Molecular Neuropsychiatry, Departments of Psychiatry and Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029
2 Andrx Laboratories, a division of Andrx Corporation, 401 Hackensack Avenue, Hackensack, NJ 07601
Academic Editor:Mark M. Smith
Front. Biosci. (Landmark Ed) 2002, 7(1), 50–59; https://doi.org/10.2741/A739
Published: 1 April 2002
(This article belongs to the Special Issue Alzheimers disease)
Abstract

Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the β-amyloid peptide (Aβ) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Aβ formation and/or clearance. To test the effects of altering cholesterol on Aβ formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Aβ formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Aβ formed. This effect was observed at concentrations of 0.05-5 µM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Aβ 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 Aβ concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Aβ 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 Aβ formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.

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