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http://purl.uniprot.org/citations/36810097http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/36810097http://www.w3.org/2000/01/rdf-schema#comment"

Background

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.

Methods

To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors.

Results

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.

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."xsd:string
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http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Chi A."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Feng X."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Clark R."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Smith B.E."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Lichtenthaler S.F."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Rose-John S."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Schumacher N."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Kennedy M.E."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Shmueli M.D."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Muller S.A."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/author"Tushaus J."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/date"2023"xsd:gYear
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/name"Mol Neurodegener"xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/pages"13"xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/title"The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130."xsd:string
http://purl.uniprot.org/citations/36810097http://purl.uniprot.org/core/volume"18"xsd:string
http://purl.uniprot.org/citations/36810097http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/36810097
http://purl.uniprot.org/citations/36810097http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/36810097
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