Acute γ-secretase inhibition of nonhuman primate CNS shifts Amyloid Precursor Protein (APP) metabolism from amyloid-β production to alternative APP fragments without amyloid-β rebound

Journal of Neuroscience

Volumn 30, Issue 19, 2010, Pages 6743-6750

  Cook, Jacquelynn J ^b   Wildsmith, Kristin R ^a   Gilberto, David B ^c   Holahan, Marie A ^b   Kinney, Gene G ^d   Mathers, Parker D ^c   Michener, Maria S ^b   Price, Eric A ^d   Shearman, Mark S ^d   Simon, Adam J ^d   Wang, Jennifer X ^a   Wu, Guoxin ^d   Yarasheski, Kevin E ^a   Bateman, Randall J ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Washington University School of Medicine ^*  (United States)

^c Laboratory Animal Resources   (United States)

^d MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; STABLE ISOTOPE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CENTRAL NERVOUS SYSTEM; CISTERNA MAGNA; CONTROLLED STUDY; ENZYME INHIBITION; HUMAN; HUMAN EXPERIMENT; IN VIVO STUDY; MALE; NONHUMAN; NORMAL HUMAN; PRIORITY JOURNAL; RHESUS MONKEY;

AMYLOID BETA-PROTEIN; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; BRAIN; CARBON RADIOISOTOPES; CROSS-OVER STUDIES; HUMANS; ISOTOPE LABELING; KINETICS; MACACA MULATTA; MALE; MODELS, ANIMAL; SPECIES SPECIFICITY; SPINAL CORD; TIME FACTORS;

EID: 77952400306     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.1381-10.2010     Document Type: Article

References (35)

1. Bateman RJ, Klunk WE (2008) Measuring target effect of proposed disease-modifying therapies in Alzheimer's disease. Neurotherapeutics 5:381-390.
2. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12:856-861.
3. Bateman RJ, Wen G, Morris JC, Holtzman DM (2007a) Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 68:666-669.
4. Bateman RJ, Munsell LY, Chen X, Holtzman DM, Yarasheski KE (2007b) Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates. J Am Soc Mass Spectrom 18:997-1006.
5. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM (2009) A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 66:48-54.
6. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer's disease. Lancet 368:387-403.
7. Burton CR, Meredith JE, Barten DM, Goldstein ME, Krause CM, Kieras CJ, Sisk L, Iben LG, Polson C, Thompson MW, Lin XA, Corsa J, Fiedler T, Pierdomenico M, Cao Y, Roach AH, Cantone JL, Ford MJ, Drexler DM, Olson RE, et al. (2008) The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression. J Biol Chem 283:22992-23003.
8. Duff K, Suleman F (2004) Transgenic mouse models of Alzheimer's disease: how useful have they been for therapeutic development? Brief Funct Genomic Proteomic 3:47-59.
9. Gilberto DB, Zeoli AH, Szczerba PJ, Gehret JR, Holahan MA, Sitko GR, Johnson CA, Cook JJ, Motzel SL (2003) An alternative method of chronic cerebrospinal fluid collection via the cisterna magna in conscious rhesus monkeys. Contemp Top Lab Anim Sci 42:53-59.
10. Golde TE (2005) The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol 15:84-87.
11. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.
12. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM (2003) Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38:547-554. (Pubitemid 36645030)
13. Lanz TA, Hosley JD, Adams WJ, Merchant KM (2004) Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-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-laninamide (LY-411575). J Pharmacol Exp Ther 309:49-55.
14. Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N, Du P, Piotrowski MA, Brown TM, Nolan CE, Richter KE, Finley JE, Fei Q, Ebbinghaus CF, Chen YL, Spracklin DK, Tate B, Geoghegan KF, Lau LF, Auperin DD, Schachter JB (2006) Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319:924-933.
15. Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, Selkoe DJ, Palmour RM, Ervin FR (2004) Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 165:283-297. (Pubitemid 38821835)
16. Maillard I, Adler SH, Pear WS (2003) Notch and the immune system. Immunity 19:781-791.
17. Michener MS, Holahan MA, Gilberto DB, Sitko GR, Shearman MS, Harrison T, Lewis H, Sankaranarayanan S, Crouthamel M, Wu G, Pietrak BL, Simon AJ, Cook JJ (2006) P2-069: nonhuman primate model for prediction of human Aβ effects. Targeting γ-secretase: effects of enzyme inhibition vs modulation of cleavage specificity on CSF and plasma Aβ in conscious rhesus monkeys. Alzheimers Dement [Suppl] 2:S252-S253.
18. Nantermet PG, Rajapakse HA, Stanton MG, Stauffer SR, Barrow JC, Gregro AR, Moore KP, Steinbeiser MA, Swestock J, Selnick HG, Graham SL, McGaughey GB, Colussi D, Lai MT, Sankaranarayanan S, Simon AJ, Munshi S, Cook JJ, Holahan MA, Michener MS, et al. (2009) Evolution of tertiary carbinamine BACE-1 inhibitors: Abeta reduction in rhesus CSF upon oral dosing. ChemMedChem 4:37-40.
19. Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon AJ, Blennow K (2009) A novel pathway for amyloid precursor protein processing. Neurobiol Aging. Advance online publication. Retrieved July 14, 2009. doi:10.1016/j.neurobiolaging.2009.06.002.
20. Rosen LB, Stone JA, Plump A, Yuan J, Harrison T, Flynn M, Dallob A, Matthews C, Stevenson D, Schmidt D, Palmieri T, Leibowitz M, Jhee S, Ereshefsky L, Salomon R, Winchell G, Shearman MS, Murphy MG, Gottesdiener KM (2006) O4-03-02: the gamma secretase inhibitor MK-0752 acutely and significantly reduces CSF Aβ40 concentrations in humans. Alzheimers Dement [Suppl] 2:S79-S79.
21. Sankaranarayanan S, Holahan MA, Colussi D, Crouthamel MC, Devanarayan V, Ellis J, Espeseth A, Gates AT, Graham SL, Gregro AR, Hazuda D, Hochman JH, Holloway K, Jin L, Kahana J, Lai MT, Lineberger J, McGaughey G, Moore KP, Nantermet P, et al. (2009) First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J Pharmacol Exp Ther 328:131-140.
22. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278:46107-46116. (Pubitemid 37432761)
23. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, May PC (2005) Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126-132. (Pubitemid 40923411)
24. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC (2006) Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66:602-604. (Pubitemid 43739900)
25. Stanger BZ, Datar R, Murtaugh LC, Melton DA (2005) Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci U S A 102:12443-12448. (Pubitemid 41266378)
26. Steiner H, Fluhrer R, Haass C (2008) Intramembrane proteolysis by gamma-secretase. J Biol Chem 283:29627-29631.
27. Struble RG, Price DL Jr, Cork LC, Price DL (1985) Senile plaques in cortex of aged normal monkeys. Brain Res 361:267-275.
28. Tomita T (2009) Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert Rev Neurother 9:661-679.
29. Vassar R (2004) BACE1: the beta-secretase enzyme in Alzheimer's disease. J Mol Neurosci 23:105-114.
30. Wolfe MS (2008a) Selective amyloid-beta lowering agents. BMC Neurosci 9 Suppl 2:S4.
31. Wolfe MS (2008b) Inhibition and modulation of gamma-secretase for Alzheimer's disease. Neurotherapeutics 5:391-398. (Pubitemid 351952492)
32. Wolfe RR, Chinkes DL, Wolfe RR (2005) Isotope tracers in metabolic research: principles and practice of kinetic analysis, Ed 2. Hoboken, NJ: Wiley.
33. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876-12882. (Pubitemid 38445862)
34. Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281:24566-24574. (Pubitemid 44274231)
35. Yarasheski KE, Smith K, Rennie MJ, Bier DM (1992) Measurement of muscle protein fractional synthetic rate by capillary gas chromatography/combustion isotope ratio mass spectrometry. Biol Mass Spectrom 21:486-490.