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

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.

Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer’s Disease and Control Mice

“…Finally, our analysis comprised a selected number of sphingolipids, e.g., S1P and seven ceramides. Though the analysis of additional sphingolipids, such as hexosylceramides and sulfatides, is undoubtedly interesting in association to FAD mutation and age ( Crivelli et al, 2020b ), we here focused on S1P and ceramide as they are important signaling sphingolipids and commercial MS standards were available for these lipids. Brain sphingosine levels were below the detection limit of our LC-MSMS setup and were therefore not reported.…”

Chlamydial Infection-Dependent Synthesis of Sphingomyelin as a Novel Anti-Chlamydial Target of Ceramide Mimetic Compounds

“…Our LC-MS/MS analysis also indicated that (1R,3S)-HPA-12, which has been widely used as a CERT inhibitor [16,[34][35][36], is converted to its phosphocholine-conjugated metabolite presumably via the cidSM-synthesis pathway and also by host SMSes (Figure 7D). Based on these data, we here suggested that (1R,3S)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of CERT or cidSM-synthesis but also via putative toxic effects of its phosphocholine adduct.…”

Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease

“…In this sense, some lipids showed statistically significant different levels between AD and non-AD groups. Specifically, an increase in gangliosides 22 , 23 , sphingomyelins (SM) 24 , 25 , lysophospholipids (LPL) 26 , 27 and monounsaturated fatty acids 28 , 29 and a decrease in sulfatides 23 , 24 were observed in AD mice compared to WT. However, these studies showed a wide variety of experimental conditions.…”