TY  - JOUR
AU  - Müller, Stephan A.
AU  - Shmueli, Merav D.
AU  - Feng, Xiao
AU  - Tüshaus, Johanna
AU  - Schumacher, Neele
AU  - Clark, Ryan
AU  - Smith, Brad E.
AU  - Chi, An
AU  - Rose-John, Stefan
AU  - Kennedy, Matthew E.
AU  - Lichtenthaler, Stefan F.
TI  - The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
JO  - Molecular neurodegeneration
VL  - 18
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2023-00286
SP  - 13
PY  - 2023
N1  - CC BY
AB  - 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.
KW  - Mice
KW  - Humans
KW  - Animals
KW  - Alzheimer Disease: drug therapy
KW  - Amyloid Precursor Protein Secretases
KW  - Cytokine Receptor gp130: therapeutic use
KW  - Aspartic Acid Endopeptidases
KW  - Interleukin-6
KW  - Nerve Tissue Proteins
KW  - IL-6 receptor subunit beta (Other)
KW  - IL-6R (Other)
KW  - Secretase (Other)
KW  - Shedding (Other)
KW  - Trans-signaling (Other)
KW  - VCAM1 (Other)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Cytokine Receptor gp130 (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - Interleukin-6 (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
KW  - Sez6 protein, mouse (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - Bace1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9942414
C6  - pmid:36810097
DO  - DOI:10.1186/s13024-023-00596-6
UR  - https://pub.dzne.de/record/255485
ER  -