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000255485 041__ $$aEnglish
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000255485 1001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A.$$b0$$eFirst author
000255485 245__ $$aThe Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
000255485 260__ $$aLondon$$bBiomed Central$$c2023
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000255485 520__ $$aThe 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.
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000255485 536__ $$0G:(GEPRIS)390857198$$aDFG project 390857198 - EXC 2145: Munich Cluster for Systems Neurology (SyNergy) (390857198)$$c390857198$$x1
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000255485 650_7 $$2Other$$aIL-6 receptor subunit beta
000255485 650_7 $$2Other$$aIL-6R
000255485 650_7 $$2Other$$aSecretase
000255485 650_7 $$2Other$$aShedding
000255485 650_7 $$2Other$$aTrans-signaling
000255485 650_7 $$2Other$$aVCAM1
000255485 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000255485 650_7 $$0133483-10-0$$2NLM Chemicals$$aCytokine Receptor gp130
000255485 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000255485 650_7 $$2NLM Chemicals$$aInterleukin-6
000255485 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000255485 650_7 $$2NLM Chemicals$$aSez6 protein, mouse
000255485 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000255485 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBace1 protein, mouse
000255485 650_2 $$2MeSH$$aMice
000255485 650_2 $$2MeSH$$aHumans
000255485 650_2 $$2MeSH$$aAnimals
000255485 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000255485 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases
000255485 650_2 $$2MeSH$$aCytokine Receptor gp130: therapeutic use
000255485 650_2 $$2MeSH$$aAspartic Acid Endopeptidases
000255485 650_2 $$2MeSH$$aInterleukin-6
000255485 650_2 $$2MeSH$$aNerve Tissue Proteins
000255485 7001_ $$0P:(DE-2719)2812458$$aShmueli, Merav D.$$b1
000255485 7001_ $$0P:(DE-2719)9000546$$aFeng, Xiao$$b2
000255485 7001_ $$0P:(DE-2719)2812852$$aTüshaus, Johanna$$b3
000255485 7001_ $$0P:(DE-HGF)0$$aSchumacher, Neele$$b4
000255485 7001_ $$0P:(DE-HGF)0$$aClark, Ryan$$b5
000255485 7001_ $$0P:(DE-HGF)0$$aSmith, Brad E.$$b6
000255485 7001_ $$0P:(DE-HGF)0$$aChi, An$$b7
000255485 7001_ $$0P:(DE-HGF)0$$aRose-John, Stefan$$b8
000255485 7001_ $$0P:(DE-HGF)0$$aKennedy, Matthew E.$$b9
000255485 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F.$$b10$$eLast author
000255485 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-023-00596-6$$gVol. 18, no. 1, p. 13$$n1$$p13$$tMolecular neurodegeneration$$v18$$x1750-1326$$y2023
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