Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [<sup>18</sup>F]FMPEP-<i>d</i><sub>2</sub> and [<sup>18</sup>F]MAGL-2102
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Notice bibliographique
Résumé
The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD).Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation.We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging.Methods: [ 18 F]FMPEP-d2 and [ 18 F]MAGL-2102 were produced on a commercial radiosynthesis module.PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (App NL-G-F ) at 3 ages, and compared to wild-type mice.Excised brains were used for in vitro autoradiography with [ 18 F]FMPEP-d2 and [ 18 F]MAGL-2102, immunofluorescence, and western blotting.Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [ 18 F]MAGL-2102 two days after ending treatment.Results: PET imaging showed sex-, age-and genotype-dependent changes in CB1 and MAGL availability.At 4-months (early-stage -amyloid pathology), female App NL-G-F mice had lower CB1 availability, and MAGL availability was increased in male App NL-G-F , compared to wild-types.At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in App NL-G-F frontal cortex, and male App NL-G-F mice exhibited higher MAGL than transgenic females brain-wide.At 12-months (late-stage -amyloid pathology), significantly lower uptake of [ 18 F]FMPEP-d2 was observed in App NL-G-F compared to wild-type, with no changes in [ 18 F]MAGL-2102 binding.App NL-G-F plaque staging was confirmed by Thioflavin-S staining.Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots.[ 18 F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice.Conclusions: The present study showed dynamic age-, sex-and pathology-related changes in CB1 and MAGL availability from early-stage -amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD.Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.
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Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle