Effect of a Novel Adenosine A2a Receptor Antagonist MB204 on Tau Hyperhosphorylation In Vivo
Bibliographic record
Abstract
BACKGROUND: Phosphorylation of Tau is a key post-translational modification implicated in tauopathies, such as Alzheimer's disease (AD), leading to microtubule dysfunction and Tau aggregation. Recent preclinical evidence suggests that deletion or pharmacological inhibition of the adenosine A2A receptor improves outcomes in both amyloid and Tau models. We recently developed a novel fluorinated derivative of the approved A2A receptor antagonist, Istradefylline (approved for Parkinson's disease), named MB204, for potential use in AD and depression. Here, we investigate the acute effects of oral MB204 on Tau phosphorylation in a non-transgenic mouse model of Tau hyperphosphorylation. METHOD: Eight-week-old CD-1 male mice (n=6 per group) were dosed with MB204 (2.5 mg/kg, p.o.) or the positive control lithium chloride (LiCl, 25.6 mg/kg, i.p.) daily for three days. One hour after the final dose, general anesthesia (1.3% isoflurane) was administered to lower body temperature and induce Tau hyperphosphorylation, as described previously. Brain tissue was collected 3 hours after anesthesia administration for quantitative western blot analysis targeting multiple Tau phosphorylation epitopes. RESULT: Multiple Tau epitopes were studied. In the cortex: reductions were seen in the phosphorylation at AT270, AT8 were seen in both MB204 and Li treatment (both p<0.001). A reduction was only seen with MB204 for pT205 (p<0.001) and only seen with lithium for the pS409 epitope (p<0.001). In the hippocampus: reductions were seen in the phosphorylation at pS40K were seen in both MB204 and Li treatment (both p<0.05 and 0.001 respectively). A reduction was only seen with MB204 for the AT8 epitope (p<0.05) and only seen for lithium for the AT270 and pT205 epitope (p<0.01 and 0.001) CONCLUSION: Acute oral treatment of mice with MB204 reduced anesthesia induced Tau hyperphosphorylation at key clinically relevant Tau epitopes. These findings highlight MB204 potential as a therapeutic agent for AD and related tauopathies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".