title: Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.
abstract: Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. erik.portelius@neuro.gu.se
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marcil
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourgeois
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nutu
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.forename: Eric
authors.initials: E
authors.lastname: Siemers
authors.forename: Kwasi G
authors.initials: KG
authors.lastname: Mawuenyega
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Sigurdson
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
mesh_terms: D000328:Adult; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001381:Azepines / Q000494:pharmacology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011480:Protease Inhibitors / Q000494:pharmacology; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D001381:Azepines; D015415:Biomarkers; 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; D010446:Peptide Fragments; D011480:Protease Inhibitors; C480626:amyloid beta-protein (1-15); C433241:amyloid beta-protein (1-16); D053829:Amyloid Precursor Protein Secretases; D000409:Alanine