A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease

Abstract

Introduction. LY450139 (semagacestat) inhibits γ-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 A1-42 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 A1-16 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 -CTF) induced by -secretase inhibition. These A isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. Trial registration. Clinical Trials.gov NCT00244322. © 2010 Portelius et al.; licensee BioMed Central Ltd.