摘要
Introduction: LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for generation of amyloid beta (A beta), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma A beta, but has no clear effect on A beta 1-40 or A beta 1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter A beta isoforms, such as A beta 1-16, 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 A beta 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 A beta isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry.
Results: The CSF levels of A beta 1-14, A beta 1-15, and A beta 1-16 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. A beta 1-40 and A beta 1-42 were unaffected by treatment.
Conclusions: CSF A beta 1-14, A beta 1-15, and A beta 1-16 increase during gamma-secretase inhibitor treatment in AD, even at doses that do not affect A beta 1-42 or A beta 1-40, probably because of increased substrate availability of the C99 APP stub (APP beta-CTF) induced by gamma-secretase inhibition. These A beta isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials.
- 出版日期2010