Home > Publications Database > The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 > print

001     255485
005     20240403131748.0
024 7 _ |a pmc:PMC9942414
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024 7 _ |a 10.1186/s13024-023-00596-6
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037 _ _ |a DZNE-2023-00286
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Müller, Stephan A.
|0 P:(DE-2719)2810938
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|e First author
245 _ _ |a The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
260 _ _ |a London
|c 2023
|b Biomed Central
336 7 _ |a article
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336 7 _ |a Journal Article
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500 _ _ |a CC BY
520 _ _ |a 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.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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|c POF4-352
|f POF IV
|x 0
536 _ _ |a DFG project 390857198 - EXC 2145: Munich Cluster for Systems Neurology (SyNergy) (390857198)
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588 _ _ |a Dataset connected to CrossRef, Journals: pub.dzne.de
650 _ 7 |a IL-6 receptor subunit beta
|2 Other
650 _ 7 |a IL-6R
|2 Other
650 _ 7 |a Secretase
|2 Other
650 _ 7 |a Shedding
|2 Other
650 _ 7 |a Trans-signaling
|2 Other
650 _ 7 |a VCAM1
|2 Other
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Cytokine Receptor gp130
|0 133483-10-0
|2 NLM Chemicals
650 _ 7 |a Aspartic Acid Endopeptidases
|0 EC 3.4.23.-
|2 NLM Chemicals
650 _ 7 |a Interleukin-6
|2 NLM Chemicals
650 _ 7 |a BACE1 protein, human
|0 EC 3.4.23.46
|2 NLM Chemicals
650 _ 7 |a Sez6 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Nerve Tissue Proteins
|2 NLM Chemicals
650 _ 7 |a Bace1 protein, mouse
|0 EC 3.4.23.46
|2 NLM Chemicals
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Alzheimer Disease: drug therapy
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases
|2 MeSH
650 _ 2 |a Cytokine Receptor gp130: therapeutic use
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases
|2 MeSH
650 _ 2 |a Interleukin-6
|2 MeSH
650 _ 2 |a Nerve Tissue Proteins
|2 MeSH
700 1 _ |a Shmueli, Merav D.
|0 P:(DE-2719)2812458
|b 1
700 1 _ |a Feng, Xiao
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700 1 _ |a Tüshaus, Johanna
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700 1 _ |a Schumacher, Neele
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700 1 _ |a Clark, Ryan
|0 P:(DE-HGF)0
|b 5
700 1 _ |a Smith, Brad E.
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700 1 _ |a Chi, An
|0 P:(DE-HGF)0
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700 1 _ |a Rose-John, Stefan
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700 1 _ |a Kennedy, Matthew E.
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700 1 _ |a Lichtenthaler, Stefan F.
|0 P:(DE-2719)2181459
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|e Last author
773 _ _ |a 10.1186/s13024-023-00596-6
|g Vol. 18, no. 1, p. 13
|0 PERI:(DE-600)2244557-2
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|t Molecular neurodegeneration
|v 18
|y 2023
|x 1750-1326
856 4 _ |y OpenAccess
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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