A Cholesterol-Lowering Drug Reduces β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

[1]  R. Servatius,et al.  Relationship between abnormal cholesterol synthesis and retarded learning in rats. , 1998, Metabolism: clinical and experimental.

[2]  S. Younkin,et al.  Glycosylphosphatidylinositol-anchored Proteins Play an Important Role in the Biogenesis of the Alzheimer’s Amyloid β-Protein* , 1999, The Journal of Biological Chemistry.

[3]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

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

[5]  T. Mizuno,et al.  Cholesterol-dependent generation of a unique amyloid beta-protein from apically missorted amyloid precursor protein in MDCK cells. , 1998, Biochimica et biophysica acta.

[6]  U. Igbavboa,et al.  Recent advances in brain cholesterol dynamics: Transport, domains, and Alzheimer's disease , 1999, Lipids.

[7]  S. Gandy,et al.  The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry. , 1996, The Journal of biological chemistry.

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

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

[10]  S. Gandy.  Neurohormonal Signaling Pathways and the Regulation of Alzheimer β-Amyloid Precursor Metabolism , 1999, Trends in Endocrinology & Metabolism.

[11]  D. Dickson,et al.  Amyloid Phenotype Characterization of Transgenic Mice Overexpressing both Mutant Amyloid Precursor Protein and Mutant Presenilin 1 Transgenes , 1999, Neurobiology of Disease.

[12]  M. Mattson.  Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. , 1997, Physiological reviews.

[13]  Ralph A. Nixon,et al.  Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease , 2000, Nature.

[14]  D J Stephens,et al.  The role of cholesterol in the biosynthesis of beta-amyloid. , 1999, Neuroreport.

[15]  R. Haley,et al.  Is there a connection between the concentration of cholesterol circulating in plasma and the rate of neuritic plaque formation in Alzheimer disease? , 2000, Archives of neurology.

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

[17]  W. Grant.  Dietary links to Alzheimer's disease: 1999 update. , 1999, Journal of Alzheimer's disease : JAD.

[18]  A. Saunders.  Apolipoprotein E and Alzheimer Disease: An Update on Genetic and Functional Analyses , 2000, Journal of neuropathology and experimental neurology.

[19]  F. H. Schmidt,et al.  Inhibition of Cholesterol Biosynthesis by BM 15.766 , 1985, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

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

[21]  I. Pastan,et al.  Effect of liposomes containing cholesterol on adenylate cyclase activity of cultured mammalian fibroblasts. , 1978, Biochimica et biophysica acta.

[22]  D. R. Gross,et al.  Link between heart disease, cholesterol, and Alzheimer's disease: A review , 2000, Microscopy research and technique.

[23]  E M Wijsman,et al.  Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease , 1995, Neurology.

[24]  J. Wahren,et al.  Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. , 1998, Journal of lipid research.

[25]  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.

[26]  F. Chevy,et al.  Cholesterol biosynthesis inhibited by BM15.766 induces holoprosencephaly in the rat. , 1997, Teratology.

[27]  K. Suzuki,et al.  Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. , 1999, The Biochemical journal.

[28]  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.

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

[30]  B. Hyman,et al.  The Lack of Accumulation of Senile Plaques or Amyloid Burden in Alzheimer's Disease Suggests a Dynamic Balance Between Amyloid Deposition and Resolution , 1993, Journal of neuropathology and experimental neurology.

[31]  R. Blumenthal.  Statins: effective antiatherosclerotic therapy. , 2000, American heart journal.

[32]  D. Lütjohann,et al.  Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol , 1997, The Journal of Biological Chemistry.

[33]  L. Fenart,et al.  A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier , 1997, The Journal of cell biology.

[34]  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.

[35]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Hofman,et al.  Dietary fat intake and the risk of incident dementia in the Rotterdam study , 1997, Annals of neurology.

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

[38]  P. Yeagle.  Modulation of membrane function by cholesterol. , 1991, Biochimie.

[39]  J. Hardy,et al.  Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes , 1998, Nature Medicine.

[40]  M. Straume,et al.  Modulation of metarhodopsin formation by cholesterol-induced ordering of bilayer lipids. , 1990, Biochemistry.

[41]  U. Igbavboa,et al.  Lipid Binding to Amyloid β‐Peptide Aggregates: Preferential Binding of Cholesterol as Compared with Phosphatidylcholine and Fatty Acids , 1997, Journal of neurochemistry.

[42]  L. Bretillon,et al.  Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. , 2000, Journal of lipid research.

[43]  B. de Strooper,et al.  Basolateral Secretion of Amyloid Precursor Protein in Madin-Darby Canine Kidney Cells Is Disturbed by Alterations of Intracellular pH and by Introducing a Mutation Associated with Familial Alzheimer's Disease (*) , 1995, The Journal of Biological Chemistry.

[44]  J. Poirier.  Apolipoprotein E in the brain and its role in Alzheimer's disease. , 1996, Journal of psychiatry & neuroscience : JPN.

[45]  Thomas Wisniewski,et al.  Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid , 1992, Neuroscience Letters.

[46]  B. Hyman,et al.  Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. , 2000, The American journal of pathology.

[47]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[48]  J. Auwerx,et al.  Genetic influences on age‐related change in total cholesterol, low density lipoprotein‐cholesterol and triglyceride levels: Longitudinal apolipoprotein E genotype effects , 1994, Genetic epidemiology.