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Fig. 1 | Molecular Neurodegeneration

Fig. 1

From: The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

Fig. 1

Proteomic analysis of non-human primate CSF. a Workflow of proteomic CSF analysis after single-dose BACE inhibition using either label free or tandem mass tag (TMT)-based quantification. b Volcano plot of BACE inhibition with 100 mg/kg (mpk) MBI-4 at 24 h (N = 3 per condition). The log2 transformed ratios are plotted against the log10 transformed p-value of the Student’s t-test. (red: proteins with p < 0.05; dashed line: FDR threshold for multiple hypotheses; N = 3). c Peptide mapping onto the topology of SEZ6, IL6ST, VCAM1, CADM4, and CSF1R using the web-based software tool QARIP [61] shows that the identified peptides are solely derived from the protein ectodomains (pink: signal peptide, blue: ectodomains yellow: transmembrane domains, green: cytoplasmic domains, black: identified peptides) d-f Dot plots for the relative MS quantification of the BACE1 substrate SEZ6 (d), the BACE1 substrate candidate IL6ST/gp130 (e) and the BACE2 substrate VCAM1 (f) at 24 h. g-h As controls, dot plots of the ADAM10 substrate CADM4 (g) and the ADAM17 substrate CSF1R (h) are shown. i Volcano plot of BACE inhibition with 3 mpk verubecestat (VB) at 24 h (vehicle N = 4; 3 mpk N = 2). j-o Dot plots for the MS quantification of the BACE1 substrate SEZ6 (j), the BACE1 substrate candidates IL6ST/gp130 (k) and TGFBR2 (l) as well as BSG (m), CADM4 (n), and CSF1R (o). (*: p < 0.05; ** p < 0.01; *** p < 0.001; red asterisks indicate significance after permutation-based FDR correction). p Western blots against shed APPβ, sSEZ6, and sgp130 in NHP CSF and against albumin (Alb) as a loading control (N = 3). q-s Dot plots for the quantification of Western blots in (p) based on the CSF of three individual NHPs at 12 (blue) and 24 h (red) post application. Shown are the mean log2 ratios of MBI-4 or Vehicle (Veh) versus the respective baseline values ± SD; For immunoblot quantification a two-way Anova test for time and dose with a Dunnett’s multiple comparisons posthoc test comparing the vehicle with the BACE inhibitor treatments was applied.*: p < 0.05; **: p < 0.01; ***: p < 0.001

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