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 A(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.