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BACE1 activity regulates cell surface contactin-2 levels

Gautam, Vivek, D’Avanzo, Carla, Hebisch, Matthias, Kovacs, Dora M, Kim, Doo Yeon·2014·Molecular Neurodegeneration
DOI 10.1186/1750-1326-9-4PMC PMC3899608
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Figure 1 BACE1 cleaves contactin-2 close to its GPI domain. A) Schematic representation of partial amino acid sequence of contactin-2 indicating putative BACE1 cleavage site. B) Graphic representation of GPI-anchored and soluble contactin-2 proteins that were used in this study. C) Lentiviral-mediated overexpression of BACE1 increased contactin-2 and sAPP shedding in CHO cells stably expressing GPI-anchored human contactin-2 (CNTN2). (D) Release of soluble contactin-2 (sCNTN2) was not changed by BACE1 overexpression. E and F) Quantitative analysis of the secreted contactin-2 levels in C) and D), respectively (Student t test; *, p < 0.05; n = 3 for each condition).
Figure 1 BACE1 cleaves contactin-2 close to its GPI domain. A) Schematic representation of partial amino acid sequence of contactin-2 indicating putative BACE1 cleavage site. B) Graphic representation of GPI-anchored and soluble contactin-2 proteins that were used in this study. C) Lentiviral-mediated overexpression of BACE1 increased contactin-2 and sAPP shedding in CHO cells stably expressing GPI-anchored human contactin-2 (CNTN2). (D) Release of soluble contactin-2 (sCNTN2) was not changed by BACE1 overexpression. E and F) Quantitative analysis of the secreted contactin-2 levels in C) and D), respectively (Student t test; *, p < 0.05; n = 3 for each condition).CC BY · PubMed Central
Figure 2 BACE1 inhibition reduces contactin-2 shedding. A) Western blot showing a sharp decrease in contactin-2 levels in CHO(CNTN2) cells treated with BACE1 Inhibitor IV. B) Quantitative analysis of the secreted contactin-2 levels in A) (Student t test; *, p < 0.05; n = 3 for each condition). C) Confocal microscopy images of cell surface contactin-2 levels in CHO cells expressing CNTN2. BACE1 Inhibitor IV induced a strong increase in contactin-2 surface levels (green). Nuclear staining with DAPI is shown in blue. Images are taken at identical settings.
Figure 2 BACE1 inhibition reduces contactin-2 shedding. A) Western blot showing a sharp decrease in contactin-2 levels in CHO(CNTN2) cells treated with BACE1 Inhibitor IV. B) Quantitative analysis of the secreted contactin-2 levels in A) (Student t test; *, p < 0.05; n = 3 for each condition). C) Confocal microscopy images of cell surface contactin-2 levels in CHO cells expressing CNTN2. BACE1 Inhibitor IV induced a strong increase in contactin-2 surface levels (green). Nuclear staining with DAPI is shown in blue. Images are taken at identical settings.CC BY · PubMed Central
Figure 3 BACE1 inhibition also decreases release of endogenous neuronal contactin-2. A) Western blot analysis of mouse primary neuronal cultures treated with 1 μM BACE 1 Inhibitor IV showed a significant decrease in contactin-2 and sAPP levels in the conditioned media. B) Quantitative analysis of secreted contactin-2 levels in A) (Student t test; **, p < 0.01; n = 3 for each condition).
Figure 3 BACE1 inhibition also decreases release of endogenous neuronal contactin-2. A) Western blot analysis of mouse primary neuronal cultures treated with 1 μM BACE 1 Inhibitor IV showed a significant decrease in contactin-2 and sAPP levels in the conditioned media. B) Quantitative analysis of secreted contactin-2 levels in A) (Student t test; **, p < 0.01; n = 3 for each condition).CC BY · PubMed Central
Figure 4 Site-directed mutagenesis of the putative BACE1 cleavage site specifically blocks contactin-2 shedding. A) Partial amino acid sequence of human contactin-2 indicating the putative BACE1 cleavage site. CNTN2-MM1008AA mutations were introduced to block BACE1 cleavage. B) Western blot analysis showing a dramatic reduction in contactin-2 release in the conditioned media of the cells expressing the BACE1-cleavage site mutant contactin-2 (CNTN2-MM1008AA). C) Quantitative analysis of secreted contactin-2 levels in B).
Figure 4 Site-directed mutagenesis of the putative BACE1 cleavage site specifically blocks contactin-2 shedding. A) Partial amino acid sequence of human contactin-2 indicating the putative BACE1 cleavage site. CNTN2-MM1008AA mutations were introduced to block BACE1 cleavage. B) Western blot analysis showing a dramatic reduction in contactin-2 release in the conditioned media of the cells expressing the BACE1-cleavage site mutant contactin-2 (CNTN2-MM1008AA). C) Quantitative analysis of secreted contactin-2 levels in B).CC BY · PubMed Central
Figure 5 BACE1 regulates surface levels of contactin-2 in mouse primary neuronal cultures. A) Western blot analysis showed that surface levels of contactin-2 were largely decreased by BACE1 overexpression in mouse primary neuronal cultures. B) Quantitative analysis of surface contactin-2 and the control N-cadherin levels in A) (Student t test; ***, p < 0.005; n = 3 for each condition). C) Western blot analysis showed that surface levels of contactin-2 were largely increased by BACE1 Inhibitor IV treatments. D) Quantitative analysis of surface contactin-2 and the control NrCAM levels in C). (Student t test; ***, p < 0.005; n = 3 for each condition).
Figure 5 BACE1 regulates surface levels of contactin-2 in mouse primary neuronal cultures. A) Western blot analysis showed that surface levels of contactin-2 were largely decreased by BACE1 overexpression in mouse primary neuronal cultures. B) Quantitative analysis of surface contactin-2 and the control N-cadherin levels in A) (Student t test; ***, p < 0.005; n = 3 for each condition). C) Western blot analysis showed that surface levels of contactin-2 were largely increased by BACE1 Inhibitor IV treatments. D) Quantitative analysis of surface contactin-2 and the control NrCAM levels in C). (Student t test; ***, p < 0.005; n = 3 for each condition).CC BY · PubMed Central
Figure 6 Contactin-2 levels are decreased in AD brain samples inversely correlating with BACE1 levels or β-amyloid plaques. A) Western blot analysis showed that contactin-2 levels were decreased in AD brain samples as compared to age-matched controls. B) Quantitative analysis of contactin-2 levels in A) (**, p < 0.01, Student’s t test; n = 9 for AD, 8 for non-AD). Contactin-2 levels were inversely correlated with BACE1 levels (C, p = 0.032, Person’s correlation test; n = 17) or amyloid plaque densities (D, p = 0.0064) in these samples.
Figure 6 Contactin-2 levels are decreased in AD brain samples inversely correlating with BACE1 levels or β-amyloid plaques. A) Western blot analysis showed that contactin-2 levels were decreased in AD brain samples as compared to age-matched controls. B) Quantitative analysis of contactin-2 levels in A) (**, p < 0.01, Student’s t test; n = 9 for AD, 8 for non-AD). Contactin-2 levels were inversely correlated with BACE1 levels (C, p = 0.032, Person’s correlation test; n = 17) or amyloid plaque densities (D, p = 0.0064) in these samples.CC BY · PubMed Central

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Metadata

Authors
Gautam, V., D’Avanzo, C., Hebisch, M., Kovacs, D. M., & Kim, D. Y.
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2014-01-09
Volume
9
Issue
1
ISSN
1750-1326
DOI
10.1186/1750-1326-9-4
PMC
PMC3899608
Cited by
46
References
3
Language
en

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