Dataset

DZNE-2025-00824

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition

Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*

2023
PRoteomics IDEntifications Database

Abstract: The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive 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 a new 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. In conclusion, 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.

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article 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*
The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
Molecular neurodegeneration 18(1), 13 (2023) [10.1186/s13024-023-00596-6]2023   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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