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

• Published in: Molecular neurodegeneration Vol. 18; no. 1; p. 13
• Main Authors: Müller, Stephan A, Shmueli, Merav D, Feng, Xiao, Tüshaus, Johanna, Schumacher, Neele, Clark, Ryan, Smith, Brad E, Chi, An, Rose-John, Stefan, Kennedy, Matthew E, Lichtenthaler, Stefan F
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.02.2023; BioMed Central; BMC
• Subjects: Acids; Alliances; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biomarkers; Cerebrospinal fluid; Clinical trials; Cognitive ability; Computer software industry; Cytokine Receptor gp130 - therapeutic use; Cytokines; Drug dosages; Glycoprotein gp130; Humans; IL-6 receptor subunit beta; IL-6R; Inflammation; Interleukin 6; Mice; Monkeys & apes; Nerve Tissue Proteins; Neurodegenerative diseases; Neurons; Peptides; Pharmacodynamics; Physiological aspects; Proteases; Proteins; Proteomics; Scientific equipment and supplies industry; Secretase; Shedding; Therapeutic targets; Trans-signaling; VCAM1; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzymes; United States; United States > US; IL-6R; Shedding; Trans-signaling; VCAM1; IL-6 receptor subunit beta; Secretase
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-023-00596-6

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.