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Göteborgs universitets publikationer

Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs.

Författare och institution:
Erik Portelius (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Bianca Van Broeck (-); Ulf Andreasson (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Mikael K Gustavsson (-); Marc Mercken (-); Henrik Zetterberg (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Herman Borghys (-); Kaj Blennow (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi)
Publicerad i:
Journal of Alzheimer's disease : JAD, 21 ( 3 ) s. 1005-12
Artikel, refereegranskad vetenskaplig
Sammanfattning (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 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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Klinisk medicin ->
Alanine, analogs & derivatives, pharmacology, Amyloid Precursor Protein Secretases, antagonists & inhibitors, metabolism, Amyloid beta-Peptides, cerebrospinal fluid, Animals, Azepines, pharmacology, Dogs, Dose-Response Relationship, Drug, Imidazoles, pharmacology, Immunoprecipitation, Mass Spectrometry, Peptide Fragments, cerebrospinal fluid, Piperidines, pharmacology
Postens nummer:
Posten skapad:
2012-06-25 15:35

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