DYRK1A INHIBITION WITH THE NOVEL THERAPEUTIC, DYR533, IN THE PS19 MOUSE MODEL OF TAUOPATHY ATTENUATES TAU PATHOLOGY, NEUROINFLAMMATION, AND SYNAPTIC FUNCTION

The prevalence of Alzheimer’s Disease (AD) and Related Dementias (ADRD) are increasing, emphasizing a need for effective therapeutic interventions. Inhibiting kinases that promote tau pathology and neuroinflammation, such as Dual-specificity tyrosine-phosphorylation related kinase 1a (Dyrk1a), are promising. We found elevated Dyrk1a expression in primary tauopathy post-mortem brain compared to healthy controls. We developed a novel, highly selective Dyrk1a inhibitor (DYR533) which significantly reduced tau hyperphosphorylation at multiple pathological epitopes and attenuated neuroinflammation in the PS19 tauopathy mouse model (Tg). We performed comparative hippocampal (Hp) tissue proteomics of Tg mice treated with increasing dose of DYR533 (1.0 and 5.0 mg/kg) against untreated vehicle controls (Tg and NonTg mice). Overall, we identified 6,513 proteins with Washc2—an endosomal sorting and transport protein— being significantly (adj. p-value <0.05) upregulated in the 5.0 mg/kg Hp group versus Tg vehicle. Gene set enrichment analysis revealed DYR533 treatment enriched processes involved in synaptic vesicle cycling and exocytosis, and postsynaptic signaling and receptor structure in Tg mice. Consistent with these findings, Dyrk1a overexpression has been shown to impair NMDA receptor–dependent long-term potentiation, suggesting that DYR533 treatment may influence proteins driving synaptic deficits. Conversely, immune system activation and regulation, apoptosis and stress response gene sets were depleted. Together, our data identify DYR533 as a modulator of tau pathology that alters proteins related to key ADRD-relevant processes, including synaptic function and immune signaling. Our ongoing studies are aimed at defining the underlying cellular mechanisms and cell specific functions of Dyrk1a (neurons vs microglia) within the brain.