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Table 1 BACE1 CSF-based biomarkers

From: β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

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
  1. Abbreviations: CSF cerebral spinal fluid, MCI individuals with mild cognitive impairment, AD patients with Alzheimer’s disease dementia, HC cognitively healthy individuals, ELISA enzyme-linked immunosorbent assay, Ab antibody, t-tau total peptide tau protein, amyloid beta, BACE1 beta secretase1