Role of dopaminergic agonists on full‐length tau protein aggregation
Bibliographic record
Abstract
Abstract Background Globally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. Dopamine receptor agonists have been used to target motor symptoms of AD [2] but there is a gap in knowledge on how these compounds play a role in tau protein aggregation. Method Herein, we propose to evaluate the use of a unique class of multivalent inhibitors with various moieties (catechol, non‐catechol, biphenyl, piperazine, and thiazole) [3] as potential inhibitors for in vitro full‐length tau protein aggregation induced by heparin. Fluorescence aggregation assay, transmission electron microscopy and 4,4′‐Dianilino‐1,1′‐binaphthyl‐5,5′‐disulfonic acid dipotassium salt (Bis‐ANS) fluorescence spectroscopy were used to obtain IC50 values, characterize the aggregation morphologies and evaluate the hydrophobicity of tau aggregates, respectively. Result The catechol containing compounds, D‐519 and D‐520, prevented aggregation of tau whereas the non‐catechol and thiazole containing compounds (D‐264 and D‐636) were poor inhibitors. Based on the inhibitors’ density function theory calculations, effective aggregation inhibitors are characterized by their high polarity and polarizability. Conclusion Data indicate that small molecule inhibitors may be useful therapeutics targeting tau aggregation related neurodegenerative diseases. References: [1] a. Andronesi, O. C., Bergen, M. V., Biernat, J., Seidel, K., Griesinger, C., Mandelkow, E., & Baldus, M. (2008). Characterization of Alzheimer’s‐like paired helical filaments from the core domain of tau protein using solid‐state NMR spectroscopy. Journal of the American Chemical Society, 130(18), 5922‐5928.; b. Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E. M., & Mandelkow, E. (2008). Proline‐directed pseudo‐phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC‐1) conformation. Journal of Biological Chemistry, 283(46), 32066‐32076. [2] Martorana, A. et al. (2013). Dopamine D2‐agonist Rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacology, 64, 108‐113. [3] Ziu, I. et al. (2020). The multifunctional dopamine D2/D3 receptor agonists also possess inhibitory activity against the full‐length tau441 protein aggregation. Bioorganic & Medicinal Chemistry, 28(18), 115667.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".