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oga inhibitor programs  (Biogen Inc)
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Biogen Inc oga inhibitor programs
<t>OGA</t> inhibitors <t>alter</t> <t>synaptic</t> plasticity. A , sample traces of whole-cell patch clamp recording of hippocampal CA1 pyramidal neurons during the first episode of paired-pulse stimulation ( A1 ) and aligned first response from every episode ( A2 ). Scale bar, 20 ms (horizontal) and 0.5pA (vertical). The color coding for DMSO (black), ASN90 ( i.e. , ASN, red), LY3372689 ( i.e. , LY, green), and MK8719 ( i.e. , MK, blue) is used in all plots. B , plots of EPSC ratio for the responses during the first episode ( B1 ) and the first responses of five episodes ( B2 ). C , LTP measured as relative EPSP slopes after the treatments of OGAi or DMSO. Left insets are sample traces pre- and post 100-Hz 1-s tetanus stimulation. Right inset is a violin plot of the average values during the last 30-s recording ( i.e. , gray box in the plot). Welch’s ANOVA test, W (DFn, DFd) = 10.61 (3.000, 17.50), p = 0.0003; Kolmogorov-Smimov test, p = 0.0063 (ASN vs. DMSO), 0.0336 (LY vs. DMSO), and 0.0063 (MK vs. DMSO). N = 3 mice and n = 3 slices ( i.e. , 9 recordings in total for every treatment). *, 0.05 > p ≥ 0.01; **, 0.01 > p ≥ 0.005; ***, 0.005 > p ≥ 0.001, ****, p < 0.001.
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OGA inhibitors alter synaptic plasticity. A , sample traces of whole-cell patch clamp recording of hippocampal CA1 pyramidal neurons during the first episode of paired-pulse stimulation ( A1 ) and aligned first response from every episode ( A2 ). Scale bar, 20 ms (horizontal) and 0.5pA (vertical). The color coding for DMSO (black), ASN90 ( i.e. , ASN, red), LY3372689 ( i.e. , LY, green), and MK8719 ( i.e. , MK, blue) is used in all plots. B , plots of EPSC ratio for the responses during the first episode ( B1 ) and the first responses of five episodes ( B2 ). C , LTP measured as relative EPSP slopes after the treatments of OGAi or DMSO. Left insets are sample traces pre- and post 100-Hz 1-s tetanus stimulation. Right inset is a violin plot of the average values during the last 30-s recording ( i.e. , gray box in the plot). Welch’s ANOVA test, W (DFn, DFd) = 10.61 (3.000, 17.50), p = 0.0003; Kolmogorov-Smimov test, p = 0.0063 (ASN vs. DMSO), 0.0336 (LY vs. DMSO), and 0.0063 (MK vs. DMSO). N = 3 mice and n = 3 slices ( i.e. , 9 recordings in total for every treatment). *, 0.05 > p ≥ 0.01; **, 0.01 > p ≥ 0.005; ***, 0.005 > p ≥ 0.001, ****, p < 0.001.

Journal: The Journal of Prevention of Alzheimer's Disease

Article Title: Synaptic toxicity of OGA inhibitors and the failure of ceperognastat

doi: 10.1016/j.tjpad.2025.100456

Figure Lengend Snippet: OGA inhibitors alter synaptic plasticity. A , sample traces of whole-cell patch clamp recording of hippocampal CA1 pyramidal neurons during the first episode of paired-pulse stimulation ( A1 ) and aligned first response from every episode ( A2 ). Scale bar, 20 ms (horizontal) and 0.5pA (vertical). The color coding for DMSO (black), ASN90 ( i.e. , ASN, red), LY3372689 ( i.e. , LY, green), and MK8719 ( i.e. , MK, blue) is used in all plots. B , plots of EPSC ratio for the responses during the first episode ( B1 ) and the first responses of five episodes ( B2 ). C , LTP measured as relative EPSP slopes after the treatments of OGAi or DMSO. Left insets are sample traces pre- and post 100-Hz 1-s tetanus stimulation. Right inset is a violin plot of the average values during the last 30-s recording ( i.e. , gray box in the plot). Welch’s ANOVA test, W (DFn, DFd) = 10.61 (3.000, 17.50), p = 0.0003; Kolmogorov-Smimov test, p = 0.0063 (ASN vs. DMSO), 0.0336 (LY vs. DMSO), and 0.0063 (MK vs. DMSO). N = 3 mice and n = 3 slices ( i.e. , 9 recordings in total for every treatment). *, 0.05 > p ≥ 0.01; **, 0.01 > p ≥ 0.005; ***, 0.005 > p ≥ 0.001, ****, p < 0.001.

Article Snippet: As Biogen’s Phase I BIIB113 study [ ] highlighted, potential impacts on synaptic transmission should be considered in the design and interpretation of clinical OGA inhibitor programs.

Techniques: Patch Clamp

OGA inhibitors alter synaptic protein levels and Tau phosphorylation. A , sample images of fluorescence immunocytochemistry for PSD95, Tuj1, GFAP, and DAPI. Scale bar, 0.5 mm. Images on the left are zoom-in images of PSD95 immunofluorescence in the cell-body layer (indicated by the white box) for all four treatments. Scale bar, 50 μm B , sample images of fluorescence immunocytochemistry for Synaptophysin 1, Tau, pTau, and DAPI. Images on the left are zoom-in images of Synaptophysin 1 immunofluorescence in the cell-body layer (indicated by the white box) for all four treatments. C & D , violin plots of PSD95 ( C ) and Synaptophysin 1 ( D ) immunofluorescence intensities. E , violin plots of pTau vs. Tau fluorescence intensity (F) ratios from the same ROIs of Synaptophysin 1. Welch’s ANOVA test for PSD95, W (DFn, DFd) = 90.96 (3.000, 2168), p < 0.0001; for Synaptophysin 1 fluorescence intensity, W (DFn, DFd) = 153.30 (3.000, 2187), p < 0.0001; for pTau/Tau, W (DFn, DFd) = 128.40 (3.000, 1918), p < 0.0001. Kolmogorov-Smimov test for all three, p < 0.0001 (ASN vs. DMSO, LY vs. DMSO, and MK vs. DMSO). N = 9 slices from 3 mice (3 ea), n = 999 ROIs (111 randomly selected from every slice). *, 0.05 > p ≥ 0.01; **, 0.01 > p ≥ 0.005; ***, 0.005 > p ≥ 0.001, ****, p < 0.001.

Journal: The Journal of Prevention of Alzheimer's Disease

Article Title: Synaptic toxicity of OGA inhibitors and the failure of ceperognastat

doi: 10.1016/j.tjpad.2025.100456

Figure Lengend Snippet: OGA inhibitors alter synaptic protein levels and Tau phosphorylation. A , sample images of fluorescence immunocytochemistry for PSD95, Tuj1, GFAP, and DAPI. Scale bar, 0.5 mm. Images on the left are zoom-in images of PSD95 immunofluorescence in the cell-body layer (indicated by the white box) for all four treatments. Scale bar, 50 μm B , sample images of fluorescence immunocytochemistry for Synaptophysin 1, Tau, pTau, and DAPI. Images on the left are zoom-in images of Synaptophysin 1 immunofluorescence in the cell-body layer (indicated by the white box) for all four treatments. C & D , violin plots of PSD95 ( C ) and Synaptophysin 1 ( D ) immunofluorescence intensities. E , violin plots of pTau vs. Tau fluorescence intensity (F) ratios from the same ROIs of Synaptophysin 1. Welch’s ANOVA test for PSD95, W (DFn, DFd) = 90.96 (3.000, 2168), p < 0.0001; for Synaptophysin 1 fluorescence intensity, W (DFn, DFd) = 153.30 (3.000, 2187), p < 0.0001; for pTau/Tau, W (DFn, DFd) = 128.40 (3.000, 1918), p < 0.0001. Kolmogorov-Smimov test for all three, p < 0.0001 (ASN vs. DMSO, LY vs. DMSO, and MK vs. DMSO). N = 9 slices from 3 mice (3 ea), n = 999 ROIs (111 randomly selected from every slice). *, 0.05 > p ≥ 0.01; **, 0.01 > p ≥ 0.005; ***, 0.005 > p ≥ 0.001, ****, p < 0.001.

Article Snippet: As Biogen’s Phase I BIIB113 study [ ] highlighted, potential impacts on synaptic transmission should be considered in the design and interpretation of clinical OGA inhibitor programs.

Techniques: Phospho-proteomics, Fluorescence, Immunocytochemistry, Immunofluorescence