Conclusion
We show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on γ-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.
Methods
An in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing.
Results
We have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1β17, 1β18 and 1β28 accompanied with a decrease of 1β25 and 1β27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection.