APLP1 as a cerebrospinal fluid biomarker for gamma-secretase modulator treatment

• Introduction: Alzheimer's disease brains are characterized by extracellular plaques containing the aggregated amyloid beta(42) (A beta(42)) peptide and intraneuronal tangles containing hyperphosphorylated tau. A beta(42) is produced by sequential processing of the amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of A beta(42). However, treatments inhibiting gamma- secretase have proven disappointing due to off-target effects. To circumvent these effects, gamma-secretase modulators (GSMs) have been developed, which rather than inhibiting gamma- secretase shift its preference into producing less aggregation-prone shorter A beta peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for gamma-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs. 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 APLP1 beta 17, 1 beta 18 and 1 beta 28 accompanied with a decrease of 1 beta 25 and 1 beta 27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection. 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 gamma-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

amyloid precursor protein

alzheimers-disease

a-beta

presenilin

cleavage

peptide

family

notch

proteolysis

deficiency

Neurosciences & Neurology

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