| 1. |
- Portelius, Erik, 1977, et al.
(författare)
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A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease
- 2010
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: INTRODUCTION: LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for generation of amyloid beta (Abeta), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Abeta, but has no clear effect on Abeta1-40 or Abeta1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Abeta isoforms, such as Abeta1-16, that in experimental settings increase during gamma-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Abeta isoforms may be biomarkers of gamma-secretase inhibitor treatment in clinical trials. METHODS: In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Abeta isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry. RESULTS: The CSF levels of Abeta1-14, Abeta1-15, and Abeta1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Abeta1-40 and Abeta1-42 were unaffected by treatment. CONCLUSIONS: CSF Abeta1-14, Abeta1-15, and Abeta1-16 increase during gamma-secretase inhibitor treatment in AD, even at doses that do not affect Abeta1-42 or Abeta1-40, probably because of increased substrate availability of the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition. These Abeta isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. TRIAL REGISTRATION: Clinical Trials.gov NCT00244322.
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| 2. |
- Portelius, Erik, 1977, et al.
(författare)
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Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.
- 2012
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 31:2, s. 335-41
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.
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