Table 1 BACE1 CSF-based biomarkers
BACE1 activity measured (method) | Antibody | Substrate | Clinical study | Result |
|---|---|---|---|---|
Sandwich ELISA | Anti-BACE1 Ab SECB1&2 [56, 57] Anti-BACE1 Ab B280 and anti-BACE1 monoclonal Ab (R&D Systems Inc) [58] | Synthetic fluorescence substrate—containing the BACE1 cleavage site | Zhong et al. [59] | Significant elevation of BACE1 levels in MCI and AD Strong and significant correlation of BACE1 activity with BACE1 protein and Aβ peptide level |
Solution-based detection of CSF BACE activity | Polyclonal NF neoepitope-specific Ab [60] | Biotinylated BACE1 substrate | Zetterberg et al. [10] | Significant differences in BACE1 activity between MCI, AD, and HC Positive correlation between BACE1 activity, CSF t-tau, and Aβ40 levels in the MCI and AD |
Sandwich ELISA | Anti-BACE1 Ab SECB1&2 [56, 57] Anti-BACE1 Ab B280 and anti-BACE1 monoclonal Ab (R&D Systems Inc) [58] | Synthetic fluorescence substrate—containing the BACE1 cleavage site [59] | Ewers et al. [11] | BACE1 activity and protein levels were significantly increased in AD compared to healthy HC Increase in CSF BACE1 activity in AD Increased activity associated with increased CSF t-tau but not Aβ42 in AD |
2 step-solution-based detection of CSF BACE activity | Anti-NF c-terminal neoepitope polyclonal Ab | Biotinylated peptide substrate (bBACE (aa1–460)) and Sapphire-II Enhancer substrate | Perneczky et al. [14] Savage et al. [15] | No significant difference in BACE1 levels between HC, MCI, and AD |
ELISA | mAbs ADx401 (clone 5G7) and 10B8 and mAb ADx402 (clone 10B8F1) biotinylated with peroxidase [26] | De Vos et al. [18] | Significant correlation of ratio of CSF neurogranin trunc P75/BACE1 between HC, MCI, and AD | |
Solution-based assay | BACE1 Activity Assay Kit (Sigma CS1060) | BACE1 Activity Assay Kit (Sigma CS1060) | Mulder et al. [16] | No significant differences in BACE1 levels between MCI, AD, and HC |
SignalClimb technology | Time-resolved fluorescence activity [61] | Synthetic TruePoint BACE1 substrate | Tsolakidou et al. [62] | Positive correlation between BACE1 activity and SORL1 in CSF t-tau and sAPPβ levels in AD |
Sandwich ELISA | Anti-BACE1 monoclonalAbs (mAbs) 5G7 and 10B8 [26] | Timmers et al. [19] | CSF BACE1 correlated positively with age (weak) and with Aβ37 (strong), sAβPP-total, p-tau181 (strong) | |
Commercially available assays | Euroimmun, Luebeck, Germany | Schaeverbeke et al. [20] | Correlation of BACE1 activity with brain volumes and Aβ load in regions typically involved early in AD | |
SignalClimb technology | Time-resolved fluorescence activity [61] | Synthetic TruePoint BACE1 substrate | Grimmer et al. [21] | Strong association between BACE1 activity and in vivo Aβ pathology in brain regions close to the ventricles |
Solution-based detection of CSF BACE activity | Polyclonal NF neoepitope-specific Ab [59] | Biotinylated BACE1 substrate | Rosén et al. [12] | BACE1 correlated slightly with sAPPα, sAPPβ, and Aβ40 |
2 step ELISA | Time-resolved fluorescence activity [61] | Synthetic TruePoint BACE1 substrate | Alexopoulos et al. [63] | No significant difference in BACE1 activity between AD and HC or MCI while BACE1 activity was significantly higher in MCI-AD compared to both HC |
Solution-based detection of CSF BACE activity | Fluorescence-based detection in the presence of inhibitor Calbiochem | Synthetic peptide substrates containing the BACE 1 cleavage site | Ewers et al. [31] | CSF BACE1 activity significantly increased in MCI compared to AD. No significant difference between AD and HC |
BACE activity fluorometric assay kit | K360-100, BioVision, Milpitas, CA, USA | Hou et al. [32] | BACE1 activity significantly increased in the hippocampus of ApoE4/3xTg mice especially in females | |
Sandwich ELISA | Used anti-BACE1 ectodomain MAB9311 (R&D Systems) and detection with rabbit anti-BACE1 N-terminus B0681 (Sigma–Aldrich) Abs [64] | Decourt et al. [42] | BACE1 levels 12% lower in the AD frontal cortex compared to HC 6.5% decrease in the temporal cortex | |
Solution-based assay | Used modified procaspase-3 as detection enzyme | Caspase substrate AspGluValAsp-p-nitroanilide | Verheijen et al. [65] | Assay detects BACE1 activity in extracts of human brain tissue and CSF |