A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.
OBJECTIVE
Accumulation of amyloid-beta (Abeta) 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 Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS.


METHODS
We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).


RESULTS
LY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance.


CONCLUSIONS
Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. batemanr@wustl.edu
Randall J
RJ
Bateman
Eric R
ER
Siemers
Kwasi G
KG
Mawuenyega
Guolin
G
Wen
Karen R
KR
Browning
Wendy C
WC
Sigurdson
Kevin E
KE
Yarasheski
Stuart W
SW
Friedrich
Ronald B
RB
Demattos
Patrick C
PC
May
Steven M
SM
Paul
David M
DM
Holtzman
D000328:Adult; D000409:Alanine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D019540:Area Under Curve; D001381:Azepines / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors; D055815:Young Adult
D016229:Amyloid beta-Peptides; D001381:Azepines; D004791:Enzyme Inhibitors; C484278: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; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine