Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS Abeta. In contrast to systemic Abeta metabolism, CNS Abeta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Abeta, including C-terminal truncated forms of Abeta: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.
Cook
Jacquelynn J
JJ
Department of Imaging, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Wildsmith
Kristin R
KR
Gilberto
David B
DB
Holahan
Marie A
MA
Kinney
Gene G
GG
Mathers
Parker D
PD
Michener
Maria S
MS
Price
Eric A
EA
Shearman
Mark S
MS
Simon
Adam J
AJ
Wang
Jennifer X
JX
Wu
Guoxin
G
Yarasheski
Kevin E
KE
Bateman
Randall J
RJ
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002250:Carbon Radioisotopes; D018592:Cross-Over Studies; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D013045:Species Specificity; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002250:Carbon Radioisotopes; D053829:Amyloid Precursor Protein Secretases
Neurotherapeutics. 2008 Jul;5(3):391-8
18625450
Nat Med. 2006 Jul;12(7):856-61
16799555
Brain Res. 1985 Dec 30;361(1-2):267-75
4084799
Science. 2002 Jul 19;297(5580):353-6
12130773
Brain Pathol. 2005 Jan;15(1):84-7
15779241
Neuron. 2003 May 22;38(4):547-54
12765607
J Am Soc Mass Spectrom. 2007 Jun;18(6):997-1006
17383190
Expert Rev Neurother. 2009 May;9(5):661-79
19402777
ChemMedChem. 2009 Jan;4(1):37-40
19085994
Lancet. 2006 Jul 29;368(9533):387-403
16876668
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12443-8
16107537
J Pharmacol Exp Ther. 2006 Nov;319(2):924-33
16920992
J Biol Chem. 2008 Oct 31;283(44):29627-31
18650432
Neurology. 2006 Feb 28;66(4):602-4
16505324
J Pharmacol Exp Ther. 2009 Jan;328(1):131-40
18854490
Contemp Top Lab Anim Sci. 2003 Jul;42(4):53-9
12906404
J Biol Chem. 2004 Mar 26;279(13):12876-82
14709552
J Biol Chem. 2003 Nov 14;278(46):46107-16
12949072
Ann Neurol. 2009 Jul;66(1):48-54
19360898
Biol Mass Spectrom. 1992 Oct;21(10):486-90
1420371
BMC Neurosci. 2008 Dec 03;9 Suppl 2:S4
19090992
J Biol Chem. 2008 Aug 22;283(34):22992-3003
18574238
Neurotherapeutics. 2008 Jul;5(3):381-90
18625449
Neurology. 2007 Feb 27;68(9):666-9
17325273
Immunity. 2003 Dec;19(6):781-91
14670296
J Mol Neurosci. 2004;23(1-2):105-14
15126696
J Pharmacol Exp Ther. 2004 Apr;309(1):49-55
14718585
Clin Neuropharmacol. 2005 May-Jun;28(3):126-32
15965311
Am J Pathol. 2004 Jul;165(1):283-97
15215183
Neurobiol Aging. 2011 Jun;32(6):1090-8
19604603
Brief Funct Genomic Proteomic. 2004 Apr;3(1):47-59
15163359
J Biol Chem. 2006 Aug 25;281(34):24566-74
16787929