Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation
Bartholomew, S. K.; Turk, J.; Winslow, W.; Foley, C.; Shaw, A.; Rokey, S.; Tallino, S.; Judd, J. M.; Beach, T. G.; Serrano, G. E.; Wilms, G.; Kushwaha, R.; McMahon, A.; Ginn, S.; Becker, W.; Hulme, C.; Dunckley, T.; Velazquez, R.
Show abstract
Alzheimers disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-{beta} (A{beta}) with limited efficacy against tau pathology and neuroinflammation--key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Picks disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Genome-wide association study and functional validation implicates JADE1 in tauopathy 97%
- Low circulating choline, a modifiable dietary factor, is associated with the pathological progression and metabolome dysfunction in Alzheimers disease. 97%
- Rare genetic variation in Fibronectin 1 (FN1) protects against APOEe4 in Alzheimer's disease 97%
Similar papers in this journal
- Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures 97%
- Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology 97%
- Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication 96%
Similar papers in this journal
- Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease 96%
- Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control 95%
- Immune receptor LAG3 regulates microglia function duringAlzheimer's disease 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.