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000271340 037__ $$aDZNE-2024-01041
000271340 041__ $$aEnglish
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000271340 1001_ $$0P:(DE-2719)2812225$$aSchmidt, Andree$$b0$$eFirst author$$udzne
000271340 245__ $$aThe Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
000271340 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2024
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000271340 520__ $$aThe β-secretase β-site APP cleaving enzyme (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 identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease.
000271340 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000271340 650_7 $$2Other$$aAging
000271340 650_7 $$2Other$$aAlzheimer disease
000271340 650_7 $$2Other$$aDrug therapy
000271340 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000271340 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000271340 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aVascular Endothelial Growth Factor Receptor-3
000271340 650_7 $$0EC 3.4.23.45$$2NLM Chemicals$$aBACE2 protein, human
000271340 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aFLT4 protein, human
000271340 650_7 $$2NLM Chemicals$$aBace2 protein, mouse
000271340 650_7 $$2NLM Chemicals$$aZebrafish Proteins
000271340 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000271340 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000271340 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000271340 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000271340 650_2 $$2MeSH$$aAnimals
000271340 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000271340 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000271340 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000271340 650_2 $$2MeSH$$aHumans
000271340 650_2 $$2MeSH$$aMice
000271340 650_2 $$2MeSH$$aVascular Endothelial Growth Factor Receptor-3: metabolism
000271340 650_2 $$2MeSH$$aVascular Endothelial Growth Factor Receptor-3: genetics
000271340 650_2 $$2MeSH$$aSignal Transduction
000271340 650_2 $$2MeSH$$aZebrafish: metabolism
000271340 650_2 $$2MeSH$$aZebrafish: genetics
000271340 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000271340 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000271340 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000271340 650_2 $$2MeSH$$aAlzheimer Disease: enzymology
000271340 650_2 $$2MeSH$$aEndothelial Cells: metabolism
000271340 650_2 $$2MeSH$$aEndothelial Cells: enzymology
000271340 650_2 $$2MeSH$$aEndothelial Cells: pathology
000271340 650_2 $$2MeSH$$aZebrafish Proteins: genetics
000271340 650_2 $$2MeSH$$aZebrafish Proteins: metabolism
000271340 7001_ $$aHrupka, Brian$$b1
000271340 7001_ $$0P:(DE-2719)9000319$$avan Bebber, Frauke$$b2$$udzne
000271340 7001_ $$aSunil Kumar, Sanjay$$b3
000271340 7001_ $$0P:(DE-2719)9000546$$aFeng, Xiao$$b4$$udzne
000271340 7001_ $$0P:(DE-2719)9000794$$aTschirner, Sarah K$$b5$$udzne
000271340 7001_ $$0P:(DE-2719)9001720$$aAßfalg, Marlene$$b6$$udzne
000271340 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b7$$udzne
000271340 7001_ $$0P:(DE-HGF)0$$aHilger, Laura Sophie$$b8
000271340 7001_ $$0P:(DE-2719)9001961$$aHofmann, Laura I$$b9$$udzne
000271340 7001_ $$0P:(DE-2719)2811056$$aPigoni, Martina$$b10$$udzne
000271340 7001_ $$0P:(DE-2719)2813355$$aJocher, Georg$$b11$$udzne
000271340 7001_ $$aVoytyuk, Iryna$$b12
000271340 7001_ $$aSelf, Emily L$$b13
000271340 7001_ $$aIto, Mana$$b14
000271340 7001_ $$aHyakkoku, Kana$$b15
000271340 7001_ $$aYoshimura, Akimasa$$b16
000271340 7001_ $$aHoriguchi, Naotaka$$b17
000271340 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b18$$udzne
000271340 7001_ $$aDe Strooper, Bart$$b19
000271340 7001_ $$aSchulte-Merker, Stefan$$b20
000271340 7001_ $$aLammert, Eckhard$$b21
000271340 7001_ $$aMoechars, Dieder$$b22
000271340 7001_ $$0P:(DE-2719)2241638$$aSchmid, Bettina$$b23$$udzne
000271340 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b24$$eLast author$$udzne
000271340 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI170550$$gVol. 134, no. 16, p. e170550$$n16$$pe170550$$tThe journal of clinical investigation$$v134$$x0021-9738$$y2024
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