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- Title
A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease.
- Authors
Portelius, Erik; Dean, Robert A.; Gustavsson, Mikael K.; Andreasson, Ulf; Zetterberg, Henrik; Siemers, Eric; Blennow, Kaj
- Abstract
Introduction: LY450139 (semagacestat) inhibits ?-secretase, a key enzyme for generation of amyloid β (Aβ), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Aβ, but has no clear effect on Aβ1-40 or Aβ1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Aβ isoforms, such as Aβ1-16, that in experimental settings increase during ?-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Aβ isoforms may be biomarkers of ?-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 Aβ isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry. Results: The CSF levels of Aβ1-14, Aβ1-15, and Aβ1-16 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. Aβ1-40 and Aβ1-42 were unaffected by treatment. Conclusions: CSF Aβ1-14, Aβ1-15, and Aβ1-16 increase during ?-secretase inhibitor treatment in AD, even at doses that do not affect Aβ1-42 or Aβ1-40, probably because of increased substrate availability of the C99 APP stub (APP β-CTF) induced by ?-secretase inhibition. These Aβ isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. Trial registration: Clinical Trials.gov NCT00244322
- Subjects
ENZYMES; AMYLOID; PEPTIDES; ALZHEIMER'S disease; CEREBROSPINAL fluid; BLOOD plasma; BIOMARKERS
- Publication
Alzheimer's Research & Therapy, 2010, Vol 2, Issue 2, p1
- ISSN
1758-9193
- Publication type
Article
- DOI
10.1186/alzrt30