Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers

McHale-Owen, Harriet; Bate, Clive

doi:10.1016/j.bbadis.2017.12.017

Cited by 6 publications

(6 citation statements)

References 53 publications

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“…Our data indicate that younger adult mice predominantly express PAFAH1b a 2 , while older mice increasingly express PAFAH1b a 1 at the protein level. These experimental data are supported by evidence that metabolism of PC(O)-PAFs is disrupted in AD (Ryan et al 2009;de Leeuw et al 2017) with Ab 42 promoting remodeling of LPC(O) to PC(O)-PAF (Ryan et al 2009;Simmons et al 2014;McHale-Owen and Bate 2018). Elevated cortical PC(O)-PAF levels have been linked mechanistically to the progression of other neuroinflammatory-associated dementias (Gelbard et al 1994;Kelesidis et al 2015).…”

Section: Discussionmentioning

confidence: 86%

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Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models

Granger

Liu

Fowler

et al. 2018

Journal of Neurochemistry

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Changes in glycerophosphocholine metabolism are observed in Alzheimer's disease; however, it is not known whether these metabolic disruptions are linked to cognitive decline. Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodeling in the hippocampus, frontal cortex, and temporal-parietal-entorhinal cortices of human amyloid beta precursor protein (ΑβPP) over-expressing mice. We identified a cortex-specific hypo-metabolic signature at symptomatic onset and a cortex-specific hyper-metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioral decline. When N5 TgCRND8 and ΑβPP /PSI mice first exhibited deficits in the Morris Water Maze, levels of lyso-phosphatidylcholines, LPC(18:0/0:0), LPC(16:0/0:0), LPC(24:6/0:0), LPC(25:6/0:0), the lyso-platelet-activating factor (PAF), LPC(O-18:0/0:0), and the PAF, PC(O-22:6/2:0), declined as a result of reduced calcium-dependent cytosolic phospholipase A α (cPLA α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPP /PSI mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age-independent. By contrast, in symptomatic N5 TgCRND8 mice, cPLA α activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA α activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b α to α expression ratio, evident in both transgenic and non-transgenic mice, reduced PAF hydrolysis thereby contributing to PAF accumulation. Taken together, these data identify distinct age-independent and age-dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioral decline in animals with pre-existing Αβ pathology. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

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Section: Discussionmentioning

confidence: 86%

“…; Simmons et al . ; McHale‐Owen and Bate ). Elevated cortical PC(O)‐PAF levels have been linked mechanistically to the progression of other neuroinflammatory‐associated dementias (Gelbard et al .…”

Section: Discussionmentioning

confidence: 99%

Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models

Granger

Liu

Fowler

et al. 2018

Journal of Neurochemistry

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“…43 It was recently reported that the inhibition of CEase reduced the concentrations of amyloid-β 42 oligomers and increased the concentrations of the corresponding monomers, which protected neurons against synapse damage. 44 Thus, MAGL and CEase seemed to be adequate enzymes for the multitarget approach together with cholinesterases and MAO-A and B. For the quantification of the MAGL and CEase activities, the chromogenic 4-nitrophenyl butyrate and the fluorogenic 4-methylumbelliferyl butyrate were used.…”

Section: Resultsmentioning

confidence: 99%

Chromenones as Multineurotargeting Inhibitors of Human Enzymes

et al. 2019

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The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).

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“…7,8 In addition, chronic inflammation has been reported to arise from dysregulation of endogenous bioactive lipids. [9][10][11][12] Accordingly, pathways regulating lipid metabolism potentially represent an important druggable axis and therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

Potential Mechanism of S. baicalensis on Lipid Metabolism Explored via Network Pharmacology and Untargeted Lipidomics

Ge¹,

Qi²,

Qu³

et al. 2021

DDDT

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Background S. baicalensis , a traditional herb, has great potential in treating diseases associated with aberrant lipid metabolism, such as inflammation, hyperlipidemia, atherosclerosis and Alzheimer’s disease. Aim of the Study To elucidate the mechanism by which S. baicalensis modulates lipid metabolism and explore the medicinal effects of S. baicalensis at a holistic level. Materials and Methods The potential active ingredients of S. baicalensis and targets involved in regulating lipid metabolism were identified using a network pharmacology approach. Metabolomics was utilized to compare lipids that were altered after S. baicalensis treatment in order to identify significantly altered metabolites, and crucial targets and compounds were validated by molecular docking. Results Steroid biosynthesis, sphingolipid metabolism, the PPAR signaling pathway and glycerolipid metabolism were enriched and predicted to be potential pathways upon which S. baicalensis acts. Further metabolomics assays revealed 14 significantly different metabolites were identified as lipid metabolism-associated elements. After the pathway enrichment analysis of the metabolites, cholesterol metabolism and sphingolipid metabolism were identified as the most relevant pathways. Based on the results of the pathway analysis, sphingolipid and cholesterol biosynthesis and glycerophospholipid metabolism were regarded as key pathways in which S. baicalensis is involved to regulate lipid metabolism. Conclusion According to our metabolomics results, S. baicalensis may exert its therapeutic effects by regulating the cholesterol biosynthesis and sphingolipid metabolism pathways. Upon further analysis of the altered metabolites in certain pathways, agents downstream of squalene were significantly upregulated; however, the substrate of SQLE was surprisingly increased. By combining evidence from molecular docking, we speculated that baicalin, a major ingredient of S. baicalensis , may suppress cholesterol biosynthesis by inhibiting SQLE and LSS, which are important enzymes in the cholesterol biosynthesis pathway. In summary, this study provides new insights into the therapeutic effects of S. baicalensis on lipid metabolism using network pharmacology and lipidomics.

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Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers

Cited by 6 publications

References 53 publications

Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models

Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models

Chromenones as Multineurotargeting Inhibitors of Human Enzymes

Potential Mechanism of S. baicalensis on Lipid Metabolism Explored via Network Pharmacology and Untargeted Lipidomics

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