Affiliations: [a] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [b] Neuroscience department, Janssen Pharmaceutica, a division of Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Correspondence:
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Correspondence to: Erik Portelius, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg S-431 80 Mölndal, Sweden. Tel.: +46 31 3432390; Fax: +46 31 3432426; E-mail: [email protected].
Abstract: Alzheimer's disease (AD) is associated with deposition of amyloid-β (Aβ) in the brain, which is reflected by low concentration of the Aβ1–42 peptide in the cerebrospinal fluid (CSF). The γ-secretase inhibitor LY450139 (semagacestat) lowers plasma Aβ1–40 and Aβ1–42 in a dose-dependent manner but has no clear effect on the CSF level of these isoforms. Less is known about the potent γ-secretase modulator E2012. Using targeted proteomics techniques, we recently identified several shorter Aβ isoforms in CSF, such as Aβ1–16, which is produced by a novel pathway. In a Phase II clinical trial on AD patients, Aβ1–14, Aβ1–15 and Aβ1–16 increased several-fold during γ-secretase inhibitor treatment. In the present study, 9 dogs were treated with a single dose of the γ-secretase modulator E2012, the γ-secretase inhibitor LY450139, or vehicle with a dosing interval of 1 week. The CSF Aβ isoform pattern was analyzed by immunoprecipitation combined with MALDI-TOF mass spectrometry. We show here that Aβ1–15 and Aβ1–16 increase while Aβ1–34 decreases in response to treatment with the γ-secretase inhibitor LY450139, which is in agreement with previous studies. The isoform Aβ1–37 was significantly increased in a dose-dependent manner in response to treatment with E2012, while Aβ1–39, Aβ1–40 and Aβ1–42 decreased. The data presented suggests that the γ-secretase modulator E-2012 alters the cleavage site preference of γ-secretase. The increase in Aβ1–37 may inhibit Aβ1–42 oligomerization and toxicity.
Keywords: Alzheimer's disease, amyloid-beta, amyloid-β protein precursor, γ-secretase, immunoprecipitation, mass spectrometry
