The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Stephan A Müller, Merav D Shmueli, Xiao Feng, Johanna Tüshaus, Neele Schumacher, Ryan Clark, Brad E Smith, An Chi, Stefan Rose-John, Matthew E Kennedy, Stefan F Lichtenthaler

Molecular neurodegeneration 2023 Feb 21

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The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans. © 2023. The Author(s).

Citation

Stephan A Müller, Merav D Shmueli, Xiao Feng, Johanna Tüshaus, Neele Schumacher, Ryan Clark, Brad E Smith, An Chi, Stefan Rose-John, Matthew E Kennedy, Stefan F Lichtenthaler. The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Molecular neurodegeneration. 2023 Feb 21;18(1):13