Acute Effect on the Aβ Isoform Pattern in CSF in Response to γ-Secretase Modulator and Inhibitor Treatment in Dogs

Abstract

Alzheimer's disease (AD) is associated with deposition of amyloid-β (Aβ) in the brain, which is reflected by low concentration of the Aβ_1–42 peptide in the cerebrospinal fluid (CSF). The γ-secretase inhibitor LY450139 (semagacestat) lowers plasma Aβ_1–40 and Aβ_1–42 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 Aβ_1–16, which is produced by a novel pathway. In a Phase II clinical trial on AD patients, Aβ_1–14, Aβ_1–15 and Aβ_1–16 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 Aβ_1–15 and Aβ_1–16 increase while Aβ_1–34 decreases in response to treatment with the γ-secretase inhibitor LY450139, which is in agreement with previous studies. The isoform Aβ_1–37 was significantly increased in a dose-dependent manner in response to treatment with E2012, while Aβ_1–39, Aβ_1–40 and Aβ_1–42 decreased. The data presented suggests that the γ-secretase modulator E-2012 alters the cleavage site preference of γ-secretase. The increase in Aβ_1–37 may inhibit Aβ_1–42 oligomerization and toxicity.