Amyloid-β_1-15/16 as a Marker for γ-Secretase Inhibition in Alzheimer's Disease

Article type: Research Article

Authors: Portelius, Erik^{a; *} | Zetterberg, Henrik^a | Dean, Robert A.^b | Marcil, Alexandre^c | Bourgeois, Philippe^c | Nutu, Magdalena^a | Andreasson, Ulf^a | Siemers, Eric^b | Mawuenyega, Kwasi G.^d | Sigurdson, Wendy C.^{d; e} | May, Patrick C.^b | Paul, Steven M.^b | Holtzman, David M.^{d; e; f} | Blennow, Kaj^a | Bateman, Randall J.^{d; e; f; *}

Affiliations: [a] Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden | [b] Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Headquarters, Indianapolis, IN, USA | [c] PerkinElmer Biosignal, Inc., Montreal, QC, Canada | [d] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA | [e] Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA | [f] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

Correspondence: [*] Correspondence to: Erik Portelius, Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, S-431 80 Mölndal, Sweden. Tel.: +46 31 343 2390; Fax: +46 31 3432426; E-mail: [email protected] and Randall Bateman, Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO, USA. Tel.: +1 314 747 7066; E-mail: [email protected].

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 Aβ1-15 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 Aβ1-15/16 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 Aβ1-15/16, Aβx-38, Aβx-40, Aβx-42, sAβPPα, and sAβPPβ. The CSF concentration of Aβ1-15/16 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 Aβx-38, Aβx-40, and Aβx-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 Aβ1-15/16 increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.

Keywords: Alzheimer's disease, amyloid-β, γ-secretase

DOI: 10.3233/JAD-2012-120508

Journal: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 335-341, 2012