Ceramide analog [18F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe

Simone M. Crivelli; Daan van Kruining; Qian Luo; Jo A.A. Stevens; Caterina Giovagnoni; Andreas Paulus; Matthias Bauwens; Dusan Berkes; Helga E. de Vries; Monique T. Mulder; Jochen Walter; Etienne Waelkens; Rita Derua; Johannes V. Swinnen; Jonas Dehairs; Felix M. Mottaghy; Mario Losen; Erhard Bieberich; Pilar Martinez-Martinez

doi:10.1038/s41598-020-76335-4

Ceramide analog [¹⁸F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe

Simone M. Crivelli, Daan van Kruining, Qian Luo, Jo A.A. Stevens, Caterina Giovagnoni, Andreas Paulus, Matthias Bauwens, Dusan Berkes, Helga E. de Vries, Monique T. Mulder, Jochen Walter, Etienne Waelkens, Rita Derua, Johannes V. Swinnen, Jonas Dehairs, Felix M. Mottaghy, Mario Losen, Erhard Bieberich, Pilar Martinez-Martinez

Physiology

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [¹⁸F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [¹⁸F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [¹⁸F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain.

Original language	English
Article number	19354
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-76335-4
State	Published - Dec 2020

Bibliographical note

Funding Information:
This work was supported by grants to MTM, JW, AR, PMM, and HEV from ZonMw Memorabel program (project nr: 733050105). The International Foundation for Alzheimer Research (ISAO) (projectnr: 14545) also supports PMM. Aspects of this work were supported by the grant NIH R01AG034389, R01NS095215, and R56AG064234; VA I01BX003643 to EB. Aspects of this work were supported by the Interreg VA EMR program (EURLIPIDS, EMR23) to EW and PM.

Publisher Copyright:
© 2020, The Author(s).

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Cite this

Crivelli, S. M., van Kruining, D., Luo, Q., Stevens, J. A. A., Giovagnoni, C., Paulus, A., Bauwens, M., Berkes, D., de Vries, H. E., Mulder, M. T., Walter, J., Waelkens, E., Derua, R., Swinnen, J. V., Dehairs, J., Mottaghy, F. M., Losen, M., Bieberich, E., & Martinez-Martinez, P. (2020). Ceramide analog [¹⁸F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe. Scientific Reports, 10(1), [19354]. https://doi.org/10.1038/s41598-020-76335-4

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title = "Ceramide analog [18F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer{\textquoteright}s disease transgenic mice by functioning as a metabolic probe",

abstract = "The metabolism of ceramides is deregulated in the brain of Alzheimer{\textquoteright}s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [18F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [18F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [18F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain.",

author = "Crivelli, {Simone M.} and {van Kruining}, Daan and Qian Luo and Stevens, {Jo A.A.} and Caterina Giovagnoni and Andreas Paulus and Matthias Bauwens and Dusan Berkes and {de Vries}, {Helga E.} and Mulder, {Monique T.} and Jochen Walter and Etienne Waelkens and Rita Derua and Swinnen, {Johannes V.} and Jonas Dehairs and Mottaghy, {Felix M.} and Mario Losen and Erhard Bieberich and Pilar Martinez-Martinez",

note = "Funding Information: This work was supported by grants to MTM, JW, AR, PMM, and HEV from ZonMw Memorabel program (project nr: 733050105). The International Foundation for Alzheimer Research (ISAO) (projectnr: 14545) also supports PMM. Aspects of this work were supported by the grant NIH R01AG034389, R01NS095215, and R56AG064234; VA I01BX003643 to EB. Aspects of this work were supported by the Interreg VA EMR program (EURLIPIDS, EMR23) to EW and PM. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41598-020-76335-4",

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Crivelli, SM, van Kruining, D, Luo, Q, Stevens, JAA, Giovagnoni, C, Paulus, A, Bauwens, M, Berkes, D, de Vries, HE, Mulder, MT, Walter, J, Waelkens, E, Derua, R, Swinnen, JV, Dehairs, J, Mottaghy, FM, Losen, M, Bieberich, E & Martinez-Martinez, P 2020, 'Ceramide analog [¹⁸F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe', Scientific Reports, vol. 10, no. 1, 19354. https://doi.org/10.1038/s41598-020-76335-4

TY - JOUR

T1 - Ceramide analog [18F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe

AU - Crivelli, Simone M.

AU - van Kruining, Daan

AU - Luo, Qian

AU - Stevens, Jo A.A.

AU - Giovagnoni, Caterina

AU - Paulus, Andreas

AU - Bauwens, Matthias

AU - Berkes, Dusan

AU - de Vries, Helga E.

AU - Mulder, Monique T.

AU - Walter, Jochen

AU - Waelkens, Etienne

AU - Derua, Rita

AU - Swinnen, Johannes V.

AU - Dehairs, Jonas

AU - Mottaghy, Felix M.

AU - Losen, Mario

AU - Bieberich, Erhard

AU - Martinez-Martinez, Pilar

N1 - Funding Information: This work was supported by grants to MTM, JW, AR, PMM, and HEV from ZonMw Memorabel program (project nr: 733050105). The International Foundation for Alzheimer Research (ISAO) (projectnr: 14545) also supports PMM. Aspects of this work were supported by the grant NIH R01AG034389, R01NS095215, and R56AG064234; VA I01BX003643 to EB. Aspects of this work were supported by the Interreg VA EMR program (EURLIPIDS, EMR23) to EW and PM. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12

Y1 - 2020/12

N2 - The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [18F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [18F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [18F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain.

AB - The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [18F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [18F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [18F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain.

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