A γ‐secretase inhibitor decreases amyloid‐β production in the central nervous system

Accumulation of amyloid‐β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Aβ production or clearance in the human CNS. The objective of this study was to determine the effects of a γ‐secretase inhibitor on the production of Aβ in the human CNS.

[1]  E. Siemers,et al.  Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. , 2007, Clinical neuropharmacology.

[2]  Dominic M. Walsh,et al.  Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease , 2004, Neuron.

[3]  A. Endo,et al.  The discovery and development of HMG-CoA reductase inhibitors. , 1992, Journal of lipid research.

[4]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[5]  A. Endo,et al.  Therapeutic effects of ML-236B in primary hypercholesterolemia. , 1980, Atherosclerosis.

[6]  Timothy Harrison,et al.  The Novel γ Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) Reduces Amyloid Plaque Deposition without Evidence of Notch-Related Pathology in the Tg2576 Mouse , 2007, Journal of Pharmacology and Experimental Therapeutics.

[7]  B. de Strooper,et al.  1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity , 2007, Journal of Pharmacology and Experimental Therapeutics.

[8]  E. Siemers,et al.  Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. , 2005, Clinical neuropharmacology.

[9]  Effects of an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase on Serum Lipoproteins and Ubiquinone-10 Levels in Patients with Familial Hypercholesterolemia , 2004 .

[10]  G. Higgins,et al.  Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. , 2004, The Journal of biological chemistry.

[11]  E. Siemers,et al.  Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers , 2005 .

[12]  H. Wen,et al.  Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities , 2007, The Journal of Neuroscience.

[13]  J. Morris,et al.  Fluctuations of CSF amyloid-β levels , 2007, Neurology.

[14]  David M Holtzman,et al.  Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo , 2006, Nature Medicine.

[15]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[16]  D. Bennett,et al.  Alzheimer disease in the US population: prevalence estimates using the 2000 census. , 2003, Archives of neurology.

[17]  J. Trojanowski,et al.  Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. , 2006, Annual review of pathology.

[18]  E. Siemers,et al.  Safety, Tolerability, and Effects on Plasma and Cerebrospinal Fluid Amyloid-&bgr; After Inhibition of &ggr;-Secretase , 2007 .

[19]  D. Holtzman,et al.  In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life , 2003, The Journal of Neuroscience.

[20]  H. Mabuchi,et al.  Effect of an inhibitor of 3-hydroxy-3-methyglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10-levels in patients with familial hypercholesterolemia. , 1981, The New England journal of medicine.

[21]  D. Dickson,et al.  Filling the Gaps in the Aβ Cascade Hypothesis of Alzheimers Disease , 2006 .

[22]  Lynn A. Hyde,et al.  Studies to Investigate the in Vivo Therapeutic Window of the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) in the CRND8 Mouse , 2006, Journal of Pharmacology and Experimental Therapeutics.

[23]  Robert A. Dean,et al.  Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease , 2006, Neurology.

[24]  F. D. Miller,et al.  Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain , 2000, Journal of neurochemistry.

[25]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[26]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[27]  D. Holtzman,et al.  Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates , 2007, Journal of the American Society for Mass Spectrometry.