|Title||A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.|
|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, DeMattos RB, May PC, Paul SM, Holtzman DM|
|Date Published||2009 Jul|
|Keywords||Adult, Alanine, Amyloid beta-Peptides, Amyloid Precursor Protein Secretases, Area Under Curve, Azepines, Central Nervous System, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme Inhibitors, Humans, Male, Middle Aged, Tandem Mass Spectrometry, Time Factors, Young Adult|
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.
INTERPRETATION: 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.
|Alternate Journal||Ann. Neurol.|
|PubMed Central ID||PMC2730994|
|Grant List||1UL1 RR024992 / RR / NCRR NIH HHS / United States |
2P60 DK020579-31 / DK / NIDDK NIH HHS / United States
5P41 RR000954-32 / RR / NCRR NIH HHS / United States
K23 AG030946 / AG / NIA NIH HHS / United States
K23 AG030946-02 / AG / NIA NIH HHS / United States
P30 DK056341-08 / DK / NIDDK NIH HHS / United States
P30 DK056341-09 / DK / NIDDK NIH HHS / United States
P41 RR000954 / RR / NCRR NIH HHS / United States
SP30 DK056341-08 / DK / NIDDK NIH HHS / United States
UL1 TR000448 / TR / NCATS NIH HHS / United States