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The beta-secretase BACE1 is a central drug target for Alzheimer’s disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we performed glycoprotein enrichment and subsequent discovery proteomics to identify substrates of the protease BACE2 in plasma of mice. Therefore, we analysed plasma from BACE2 KO, BACE1/2 double KO and WT controls, as well as BACE1 KO with a separate WT control. Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3/FLT4. Thus, sVEGFR3 represents a pharmacodynamic plasma marker for BACE2 activity in vivo.
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Created: 5th Jul 2024 at 07:29
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Projects: SyNergy - Published Datasets
Institutions: DZNE
Projects: SyNergy - Published Datasets, HTRA1
Institutions: Klinikum der Universität München
Projects: SyNergy - Published Datasets
Institutions: DZNE
Public web page: Not specified
Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa, Danio rerio
Submitter: Rainer Malik
Studies: A TBK1 variant causes autophagolysosomal and motoneuron pathology withou..., ACSL3 is a novel GABARAPL2 interactor that links ufmylation and lipid dr..., ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte D..., ALS-linked loss of Cyclin-F function affects HSP90, AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal..., ATG4 family proteins drive phagophore growth independently of the LC3/GA..., An optimized quantitative proteomics method establishes the cell type-re..., Autophagosomal Content Profiling Reveals an LC3C-Dependent Piecemeal Mit..., Autophagosome content profiling using proximity biotinylation proteomics..., Autophagy acts through TRAF3 and RELB to regulate gene expression via an..., Basic Fibroblast Growth Factor 2-Induced Proteome Changes Endorse Lewy B..., Beneficial Effect of ACI-24 Vaccination on Aβ Plaque Pathology and Micro..., Brain injury environment critically influences the connectivity of trans..., C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin c..., CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boos..., Cell-type-specific profiling of brain mitochondria reveals functional an..., Deciphering sources of PET signals in the tumor microenvironment of glio..., Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regula..., Excessive local host-graft connectivity in aging and amyloid-loaded brain, Experimental evidence for temporal uncoupling of brain Aβ deposition and..., Fibrillar Aβ triggers microglial proteome alterations and dysfunction in..., Filling the Gaps – A Call for Comprehensive Analysis of Extracellular Ma..., IKKβ binds NLRP3 providing a shortcut to inflammasome activation for rap..., Injury-specific factors in the cerebrospinal fluid regulate astrocyte pl..., Lipid and protein content profiling of isolated native autophagic vesicles, Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in..., Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH, Lysosomal targeting of the ABC transporter TAPL is determined by membran..., Mapping autophagosome contents identifies interleukin-7 receptor-alpha a..., Met/HGFR triggers detrimental reactive microglia in TBI, Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD..., Multiomic ALS signatures highlight subclusters and sex differences sugge..., Neuronal differentiation of LUHMES cells induces substantial changes of ..., NrCAM is a marker for substrate-selective activation of ADAM10 in Alzhei..., Pro-inflammatory activation following demyelination is required for myel..., Proteomic and lipidomic profiling of demyelinating lesions identifies fa..., Proteomic profiling in cerebral amyloid angiopathy reveals an overlap wi..., Proteomics of mouse brain endothelium uncovers dysregulation of vesicula..., Rational correction of pathogenic conformational defects in HTRA1, Reactivated endogenous retroviruses promote protein aggregate spreading, Signal peptide peptidase-like 2c impairs vesicular transport and cleaves..., Signatures of glial activity can be detected in the CSF proteome, Spatial centrosome proteome of human neural cells uncovers disease-relev..., Spatial proteomics in three-dimensional intact specimens, Spatial proteomics reveals secretory pathway disturbances caused by neur..., Systematically defining selective autophagy receptor-specific cargo usin..., Targeting the TCA cycle can ameliorate widespread axonal energy deficien..., The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 si..., The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulat..., The COP9 signalosome reduces neuroinflammation and attenuates ischemic n..., The Hippo network kinase STK38 contributes to protein homeostasis by inh..., The intramembrane protease SPPL2c promotes male germ cell development by..., The pseudoprotease iRhom1 controls ectodomain shedding of membrane prote..., The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor com..., The ubiquitin-conjugating enzyme UBE2QL1 coordinates lysophagy in respon..., Trnp1 organizes diverse nuclear membrane-less compartments in neural ste..., Ubiquitin profiling of lysophagy identifies actin stabilizer CNN2 as a t...
Assays: Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Bottom-up proteomics (mouse), Gel-based experiment (human), Phosphoproteomics / Bottom-up proteomics (mouse), Proximity-proteomics-based autophagosome content profiling (human), SWATH MS (human), SWATH MS (mouse), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (macaque), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (rat), Untargeted Proteomics (mouse)
Snapshots: Snapshot 1
Submitter: Rainer Malik
Assay type: Proteomics
Technology type: Technology Type
Investigation: Proteomics
Organisms: Mus musculus
SOPs: No SOPs
Data files: Plasma proteomics of BACE1, 2, and double KO mice, Plasma proteomics of BACE2 KO mice, Plasma proteomics of mice treated with BACE inh...
Snapshots: No snapshots
The Beta-secretase BACE1 is a central drug target for Alzheimer’s disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. To discover potential BAC2 substrates in plasma, mice were treated with a non-specific BACE inhibitor (Cpd89) and a BACE1 preferring inhibitor (LY2811376). Plasma proteomics using DIA showed a reduced abundance of soluble FLT4 (sVEGFR3) for the non-specific ...
Creator: Rainer Malik
Submitter: Rainer Malik
Investigations: Proteomics
Studies: The Alzheimer's disease-linked protease BACE2 c...
Assays: Shotgun proteomics (mouse)
The beta-secretase BACE1 is a central drug target for Alzheimer’s disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we performed discovery proteomics to identify substrates of the protease BACE2 in plasma of mice. Therefore, we analysed plasma from BACE2 KO, and WT controls. Inactivation of BACE2 inhibited shedding of VEGFR3/FLT4. Thus, sVEGFR3 represents a ...
Creator: Rainer Malik
Submitter: Rainer Malik
Investigations: Proteomics
Studies: The Alzheimer's disease-linked protease BACE2 c...
Assays: Shotgun proteomics (mouse)
The beta-secretase BACE1 is a central drug target for Alzheimer’s disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we performed glycoprotein enrichment and subsequent discovery proteomics to identify substrates of the protease BACE2 in plasma of mice. Therefore, we analysed plasma from BACE2 KO, BACE1/2 double KO and WT controls, as well as BACE1 KO with a separate ...
Creator: Rainer Malik
Submitter: Rainer Malik
Investigations: Proteomics
Studies: The Alzheimer's disease-linked protease BACE2 c...
Assays: Shotgun proteomics (mouse)
Abstract (Expand)
Authors: A. Schmidt, B. Hrupka, F. van Bebber, S. Sunil Kumar, X. Feng, S. K. Tschirner, M. Assfalg, S. A. Muller, L. S. Hilger, L. I. Hofmann, M. Pigoni, G. Jocher, I. Voytyuk, E. L. Self, M. Ito, K. Hyakkoku, A. Yoshimura, N. Horiguchi, R. Feederle, B. De Strooper, S. Schulte-Merker, E. Lammert, D. Moechars, B. Schmid, S. F. Lichtenthaler
Date Published: 18th Jun 2024
Publication Type: Journal
PubMed ID: 38888964
Citation: J Clin Invest. 2024 Jun 18:e170550. doi: 10.1172/JCI170550.