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
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".