Journal Article

DZNE-2023-00286

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

Müller, S. A. (First author)DZNE* ; Shmueli, M. D.DZNE* ; Feng, X.DZNE* ; Tüshaus, J.DZNE* ; Schumacher, N. ; Clark, R. ; Smith, B. E. ; Chi, A. ; Rose-John, S. ; Kennedy, M. E. ; Lichtenthaler, S. F. (Last author)DZNE*

2023
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s13024-023-00596-6

Abstract: 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.

Keyword(s): Mice (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Amyloid Precursor Protein Secretases (MeSH) ; Cytokine Receptor gp130: therapeutic use (MeSH) ; Aspartic Acid Endopeptidases (MeSH) ; Interleukin-6 (MeSH) ; Nerve Tissue Proteins (MeSH) ; IL-6 receptor subunit beta ; IL-6R ; Secretase ; Shedding ; Trans-signaling ; VCAM1 ; Amyloid Precursor Protein Secretases ; Cytokine Receptor gp130 ; Aspartic Acid Endopeptidases ; Interleukin-6 ; BACE1 protein, human ; Sez6 protein, mouse ; Nerve Tissue Proteins ; Bace1 protein, mouse

Note: CC BY

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. DFG project 390857198 - EXC 2145: Munich Cluster for Systems Neurology (SyNergy) (390857198) (390857198)

Appears in the scientific report 2023

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Database coverage:
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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition
PRoteomics IDEntifications Database (2023)2023   Fulltext BibTeX | EndNote: XML, Text | RIS

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