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

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.

[1]  D. Selkoe,et al.  Receptor-Mediated Transport of Human Amyloid β-Protein 1–40 and 1–42 at the Blood–Brain Barrier , 1999, Neurobiology of Disease.

[2]  J. Marx.  Bad for the Heart, Bad For the Mind? , 2001, Science.

[3]  E. Kojro,et al.  Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  I. Lieberburg,et al.  This paper was presented at the National Academy of Sciences colloquium ''Proteolytic Processing and Physiological Regulation,'' held February 20-21, 1999, at the Arnold and Mabel Beckman Center in Irvine, CA. Cellular mechanisms of b-amyloid production and secretion , 1999 .

[5]  R. Brasseur,et al.  β‐Amyloid Peptide Interacts Specifically with the Carboxyl‐Terminal Domain of Human Apolipoprotein E , 1999, Journal of Neurochemistry.

[6]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[8]  J. Buxbaum,et al.  Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. , 2001, The international journal of neuropsychopharmacology.

[9]  Joseph D. Buxbaum,et al.  Evidence That Tumor Necrosis Factor α Converting Enzyme Is Involved in Regulated α-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor* , 1998, The Journal of Biological Chemistry.

[10]  E. Kojro,et al.  Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  K. Davis,et al.  Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. , 2000, JAMA.

[12]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[13]  Stephen W. Scheff,et al.  Induction of Alzheimer-like β-Amyloid Immunoreactivity in the Brains of Rabbits with Dietary Cholesterol , 1994, Experimental Neurology.

[14]  J. Dichgans,et al.  Cholesterol and Alzheimer’s disease , 2001, Neurology.

[15]  R. Mayeux,et al.  APOE genotype, plasma lipids, lipoproteins, and AD in community elderly , 1999, Neurology.

[16]  J. Bading,et al.  Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy , 1998, Journal of neurochemistry.

[17]  P. Greengard,et al.  Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D L Price,et al.  Alzheimer's disease: genetic studies and transgenic models. , 1998, Annual review of genetics.

[19]  Brian J Cummings,et al.  β-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease , 1996, Neurobiology of Aging.

[20]  B. Strooper,et al.  Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  B. Zlokovic,et al.  Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. , 1998, The Journal of clinical investigation.

[22]  R. Martins,et al.  Apolipoprotein E promotes the binding and uptake of β-amyloid into Chinese hamster ovary cells in an isoform-specific manner , 1999, Neuroscience.

[23]  K. Davis,et al.  Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. , 1998, Archives of neurology.

[24]  M. Emmerling,et al.  High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease. , 1999, Biochemical and biophysical research communications.

[25]  C. Bergmann,et al.  Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  A. Nissinen,et al.  Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. , 1998, Neuroepidemiology.

[27]  Brian,et al.  THE ROLE OF CHOLESTEROL IN BIOSYNTHESIS OF β-AMYLOID , 1999 .

[28]  B. Greenberg,et al.  Modulation of Secreted β-Amyloid Precursor Protein and Amyloid β-Peptide in Brain by Cholesterol* , 1998, The Journal of Biological Chemistry.

[29]  S. Lavrentiadou,et al.  Contribution of cysteine 158, the glycosylation site threonine 194, the amino- and carboxy-terminal domains of apolipoprotein E in the binding to amyloid peptide beta (1-40). , 1999, Biochemistry.

[30]  R. Knopp.  Drug treatment of lipid disorders. , 1999, The New England journal of medicine.

[31]  H Jick,et al.  Statins and the risk of dementia , 2000, The Lancet.

[32]  David J. Cummins,et al.  Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Mercken,et al.  A Cholesterol-Lowering Drug Reduces β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease , 2001, Neurobiology of Disease.

[34]  G. Celesia,et al.  Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. , 2000, Archives of neurology.

[35]  C. Broeckhoven,et al.  Molecular genetic analysis of Alzheimer's disease , 1995 .

[36]  K. Davis,et al.  Correlation Between Aβx-40–, Aβx-42–, and Aβx-43–Containing Amyloid Plaques and Cognitive Decline , 2001 .

[37]  Rong Wang,et al.  Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model , 2000, Neurobiology of Disease.

[38]  W. Klein,et al.  Cholesterol Modulates -Secretase Cleavage of Amyloid Precursor Protein (*) , 1996, The Journal of Biological Chemistry.

[39]  D. Riddell,et al.  Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts , 2001, Current Biology.

[40]  G. Forloni,et al.  Cholesterol decreases secretion of the secreted form of amyloid precursor protein by interfering with glycosylation in the protein secretory pathway. , 2000, The Biochemical journal.

[41]  J. Poirier,et al.  Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures. , 1999, Brain research. Molecular brain research.

[42]  J. Buxbaum,et al.  Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide. , 2001, Journal of Alzheimer's disease : JAD.

[43]  B. Wolozin.  A fluid connection: Cholesterol and Aβ , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Motter,et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse , 1999, Nature.

[45]  B. Hyman,et al.  Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide , 2001, Nature Cell Biology.

[46]  P. Greengard,et al.  Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. , 1994, Proceedings of the National Academy of Sciences of the United States of America.