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.
Highlights
The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) apolipoprotein E4 (APOE4) and amyloid-β pathology
We report that the [18F]F-HPA-12 dynamics, in vivo, is different in FAD mice brains compared to control
Metabolic analysis of the brain suggested that the higher levels of [18F]F-HPA-12 were due to a slower degradation of the tracer in the brain of FAD mice
Summary
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. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain. The global levels of specific ceramide species extracted from middle frontal gyrus, temporal gyrus, inferior parietal lobe, and hippocampus are elevated in AD patients compared to healthy controls[4,5,6] Whether these observations pertaining to the pathophysiology of AD are causative or a subsequent event, is still unclear. The levels of ceramide in cerebral spinal fluid correlates with the concentration of some forms of amyloid-β (Aβ), like Aβ1-38 and Aβ1-40, in individuals at high risk of developing AD This suggests early involvement of ceramide in the pathogenesis of the d isease[11,12]. Littermates not carrying AD mutated genes APP/PSEN1 were used as controls
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