Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs.
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.
Portelius
Erik
E
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. erik.portelius@neuro.gu.se
Van Broeck
Bianca
B
Andreasson
Ulf
U
Gustavsson
Mikael K
MK
Mercken
Marc
M
Zetterberg
Henrik
H
Borghys
Herman
H
Blennow
Kaj
K
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010880:Piperidines / Q000494:pharmacology*
C555019:1-(1-(4-fluorophenyl)ethyl)-3-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)methylene)-2-piperidinone; D016229:Amyloid beta-Peptides; D001381:Azepines; D007093:Imidazoles; 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; D010880:Piperidines; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine