Dataset Information

Plasma proteomics of mice treated with BACE inhibitors

ABSTRACT: 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 inhbtor but not for the BACE1 preferring inhibitor. Conclusively, sVEGFR3 is a potential marker for BACE2 inhibition in plasma.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan F. Lichtenthaler

PROVIDER: PXD042669 | Pride | 2024-06-27

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 44

Publications

The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

Schmidt Andree A Hrupka Brian B van Bebber Frauke F Sunil Kumar Sanjay S Feng Xiao X Tschirner Sarah K SK Aßfalg Marlene M Müller Stephan A SA Hilger Laura Sophie LS Hofmann Laura I LI Pigoni Martina M Jocher Georg G Voytyuk Iryna I Self Emily L EL Ito Mana M Hyakkoku Kana K Yoshimura Akimasa A Horiguchi Naotaka N Feederle Regina R De Strooper Bart B Schulte-Merker Stefan S Lammert Eckhard E Moechars Dieder D Schmid Bettina B Lichtenthaler Stefan F SF

The Journal of clinical investigation 20240618 16

The 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 ...[more]

PMID: 38888964

Similar Datasets

Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).

			Action	DRS
	LY_CPD89_LFQ.xlsx	Xlsx
	MTS_LY_Spectronaut_output.sne	Other
	Mouse_plasma_optimized_OldLC.xls	Xls
	checksum.txt	Txt
	plasma_01.raw	Raw