000279497 001__ 279497
000279497 005__ 20250709100939.0
000279497 037__ $$aDZNE-2025-00824
000279497 1001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b0$$udzne
000279497 245__ $$aDataset: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition
000279497 260__ $$bPRoteomics IDEntifications Database$$c2023
000279497 3367_ $$2BibTeX$$aMISC
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000279497 520__ $$aThe protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as a new in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. In conclusion, BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.
000279497 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000279497 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan$$b1$$udzne
000279497 7870_ $$0DZNE-2023-00286$$aMüller, Stephan A. et.al.$$dLondon : Biomed Central, 2023$$iRelatedTo$$r$$tThe Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
000279497 8564_ $$uhttps://wwwdev.ebi.ac.uk/pride/archive/projects/PXD035141
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000279497 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810938$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000279497 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2181459$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE
000279497 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000279497 9201_ $$0I:(DE-2719)1110006$$kAG Lichtenthaler$$lNeuroproteomics$$x0
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