Dataset Information

Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition

ABSTRACT: The 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Macaca Mulatta (rhesus Macaque)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan F. Lichtenthaler

PROVIDER: PXD035141 | Pride | 2023-02-23

REPOSITORIES: Pride

ACCESS DATA

Publications

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Müller Stephan A SA Shmueli Merav D MD Feng Xiao X Tüshaus Johanna J Schumacher Neele N Clark Ryan R Smith Brad E BE Chi An A Rose-John Stefan S Kennedy Matthew E ME Lichtenthaler Stefan F SF

Molecular neurodegeneration 20230221 1

<h4>Background</h4>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.<h4>Methods</h4>To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors.<h4>Results</h4>Besides SEZ6, the strongest, dose-dependent reduction wa ...[more]

PMID: 36810097

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
	D17.raw	Raw
	D21.raw	Raw
	D31.raw	Raw
	D33.raw	Raw
	D37.raw	Raw

Dataset Information

Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition

Dataset's files

Publications

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets