Table 1. Changes in protein secretion and shedding upon BACE1 inhibitor C3 treatment
Protein nameIPIaMeanbs.e.m.cVSdPepteProtein typef
Membrane proteins showing reduced shedding upon C3 treatment
Seizure protein 6‐like 1IPI006742410.040.011.28E−0213Type I
Seizure protein 6IPI003807490.080.033.08E−0219Type I
Amyloid precursor‐like protein 1IPI001292490.110.022.32E−0227Type I
VWFA and cache domain‐containing protein 1IPI003504250.120.121.31E−016Type I
Golgi apparatus protein 1IPI001223990.210.056.69E−0211Type I
L1IPI007853710.210.033.79E−0224Type I
Leucine‐rich repeat neuronal protein 1IPI001260700.250.067.69E−027Type I
Plexin domain‐containing protein 2IPI004711790.250.101.38E−013Type I
NeurotriminIPI004170050.330.142.08E−016GPI
Cell adhesion molecule with homology to L1CAMIPI008315460.350.057.25E−0249Type I
Peptidyl‐glycine α‐amidating monooxygenaseIPI003239740.360.121.83E−0123Type I
Alpha‐1,4‐N‐acetylhexosaminyltransferase EXTL2IPI001129000.360.162.47E−015Type II
Protocadherin γ A11IPI001296860.420.152.56E−017Type I
Amyloid precursor‐like Protein 2IPI001213380.430.091.57E−0120Type I
ST3GAL‐I sialyltransferaseIPI001088490.440.172.98E−013Type II
Latrophilin‐1IPI009187240.450.101.79E−0119Polytopic
Neuroligin 4IPI008582770.450.081.38E−0122Type I
Semaphorin‐6DIPI003967590.470.091.70E−013Type I
Lysosomal membrane glycoprotein 1IPI004692180.480.163.14E−012Type I
Neurexin I‐αIPI004685390.510.047.94E−0230Type I
Protocadherin‐20IPI002222780.520.163.22E−0110Type I
Latrophilin‐3IPI004111570.530.102.09E−017Polytopic
Latrophilin‐2IPI008765580.560.102.17E−0110Polytopic
Sodium/potassium‐dependent ATPase subunit β‐1IPI001215500.570.143.33E−013Type II
Delta and Notch‐like epidermal growth factor‐related receptorIPI001703420.570.092.19E−013Type I
Interferon α/β receptor 2IPI003952090.580.122.84E−014Type I
Neuroligin‐2IPI004686050.580.112.55E−0116Type I
Seizure 6‐like protein 2IPI001284540.600.143.41E−0113Type I
Leucine‐rich repeat and fibronectin type‐III domain‐containing protein 2IPI003301520.620.133.37E−014Type I
CX3C membrane‐anchored chemokineIPI001278110.640.112.97E−014Type I
Contactin‐2IPI001199700.640.061.81E−0139GPI
Amyloid precursor proteinIPI001143890.670.082.44E−0130Type I
Neuroligin‐1IPI003091130.730.082.86E−0113Type I
Transmembrane protein 132AIPI004641510.820.063.45E−0138Type I
Soluble proteins reduced upon C3 treatment
Activin β‐B chainIPI003551340.140.088.87E−027Secreted
Adamts3IPI006728990.300.182.53E−017Secreted
Insulin‐like growth factor‐binding protein 2IPI003133270.410.122.10E−012Secreted
Extracellular matrix protein 1IPI008899480.490.132.63E−015Secreted
Neuronal olfactomedin‐related ER localized proteinIPI001367120.500.122.28E−0110Secreted
ReelinIPI001214210.850.042.87E−0121Secreted
Selection of proteins unaltered upon C3 treatment
Hepatocyte growth factor receptorIPI001304200.830.137.60E−018Type I
NeogeninIPI001291590.900.098.56E−0133Type I
Protocadherin‐γ C3IPI001296130.810.136.86E−0112Type I
Receptor‐type tyrosine‐protein phosphatase sigmaIPI002300670.900.191.90E+0020Type I
Leucine‐rich repeat‐containing protein 4BIPI003810590.910.182.13E+0020Type I
Netrin receptor DCCIPI001373471.000.181.38E+0231Type I
Prostaglandin F2 receptor‐negative regulatorIPI005153190.850.151.04E+0029Type I
Neural cell adhesion molecule 1IPI001229710.990.161.12E+0128Type I
  • a IPI accession number of the protein.

  • b Mean ratio between BACE1 inhibitor treatment (C3) and control (DMSO) conditions of the summed unique peptides intensities identified for a unique protein group for five biological replicates (C3/DMSO) shows remaining ectodomain levels upon BACE1 inhibition. SPECS values for remaining shedding of APP (0.67=67%), APLP1 (0.11=11%) and APLP2 (0.42=42%) correspond well to the literature. In neurons, APLP1 is mainly cleaved by BACE1 (Sala Frigerio et al, 2010), whereas APLP2 shedding is mediated to about 60% by BACE1 (Hogl et al, 2011). In contrast, total APP shedding was only mildly inhibited with C3, because it is known that inhibition of BACE1 cleavage of APP is accompanied by an increase in the ADAM10‐mediated cleavage, resulting in only a moderate inhibition of total APP shedding upon BACE1 inhibition (Vassar et al, 1999; May et al, 2011).

  • c Standard error of the mean for five biological replicates.

  • d Variance score was calculated for all proteins. Proteins with a variance score of ≤0.35 were considered as proteins with a consistent change under BACE1 inhibition.

  • e Number of identified peptides of the protein group.

  • f Protein type: Secreted: Secreted, soluble protein, Type I: type I membrane protein, Type II: type II membrane protein, Polytopic: membrane protein with multiple transmembrane domains, GPI: GPI‐anchored membrane protein.