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Fig. 5 | Molecular Neurodegeneration

Fig. 5

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

Fig. 5

IL6 trans signaling in neurons is affected by BACE1 inhibition. a Classical and trans-signaling of IL-6. In classical signaling, IL-6 binds to the transmembrane IL-6R. The IL-6/IL-6R complex associates with the signal transducing protein gp130, initiating intracellular signaling involving the phosphorylation of STAT3 and downstream transcription. In trans-signaling, a soluble form of IL-6R (sIL-6R) is proteolytically released by the metalloprotease ADAM10/17 or by alternative splicing from specific cells (such as microglia in the brain). sIL-6R binds IL-6 to form a complex that signals through gp130. The BACE1-cleaved sgp130 ectodomain can also bind to the IL-6/IL-6R complex and specifically inhibit trans-signaling without affecting classic IL-6 signaling. b immunoblots for phosphorylated STAT3 (p-STAT3) and STAT3 in neuronal lysates following activation of trans-signaling with 10 ng/ml of the IL-6/IL6R complex fusion protein hyper IL-6 (H-IL-6) for 15 min, in the presence or absence of BACE inhibitor C3. For the rescue experiment, H-IL-6 was preincubated with sgp130 before the addition. Actin serves as loading control. c Quantification of p-STAT3/total STAT3 ratio in samples from b (N = 6 biological replicates). Shown are mean ± SD. Unpaired Student t-test. d Immunoblots against the indicated proteins in neurons transduced with lentiviruses expressing scrambled (SCR) control shRNA or two distinct shRNAs against gp130 (shRNA1, shRNA2). Activation of gp130 signaling with H-IL-6 was done as in b. e Immunoblots against indicated proteins in floxed BACE1 (Ctrl) or BACE1−/− neurons (lentivirally Cre-transduced). Activation of gp130 signaling with H-IL-6 and rescue with sg130 was done as in b. f Quantification of p-STAT3/total STAT3 ratio in samples from e (N = 6 biological replicates). Shown are mean ± SD. One-way ANOVA with post hoc Tukey’s multiple comparison test. g MTT measurement of primary neurons at DIV12 after culture in the absence of serum-like B27 and in the absence or presence of BACE inhibitor C3 upon activation with H-IL-6 or rescue with sgp130. Shown are mean ± SD from N = 24 biological replicates. One-way ANOVA with post hoc Tukey’s multiple comparison test. *: p < 0.05; ***: p < 0.001; ****: p < 0.0001

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