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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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.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Crivelli, Simone M.; van Kruining, Daan; Luo, Qian; Stevens, Jo A. A.; Giovagnoni, Caterina; Paulus, Andreas; Bauwens, Matthias; Berkes, Dusan; de Vries, Helga E.; Mulder, Monique T.; Walter, Jochen; Waelkens, Etienne; Derua, Rita; Swinnen, Johannes V.; Dehairs, Jonas; Mottaghy, Felix M.; Losen, Mario; Bieberich, Erhard; and Martinez-Martinez, Pilar, "Ceramide Analog [18F]F-HPA-12 Detects Sphingolipid Disbalance in the Brain of Alzheimer’s Disease Transgenic Mice by Functioning as a Metabolic Probe" (2020). Physiology Faculty Publications. 162.