Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice

Abstract

Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10. In the present study, we investigated the regulation of endogenous tau exon 10 splicing by Dyrk1A. We found that inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome. Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains. Thus, Dyrk1A might be an ideal therapeutic target for Alzheimer’s disease, especially for Down syndrome and EGCG which inhibits Dyrk1A may have potential effect on the treatment or prevention of this disease.

Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice

“…The varied results in the different brain regions and bone after EGCG treatment may reflect a more broad inhibitory mechanism of EGCG than just decreasing DYRK1A activity 6,7,51 . The results from these and other studies suggest that three copies of Dyrk1a lead to overexpression of DYRK1A protein in some but not all tissues and may be dependent on developmental time 52 , as DYRK1A levels in forebrain from Ts65Dn mice decreased from postnatal day 5 through day 35 53 . Increased DYRK1A levels and activity in this and other studies indicates that, although EGCG may not lower DYRK1A activity in vivo, trisomic DYRK1A may still be a viable target for skeletal and cognitive phenotypes associated with DS 18,51,52 .…”

“…The cognitive and behavioral tasks were administered as previously described 22,23 . Starting on PD 49, mice underwent two days of testing on the multivariate concentric square field maze (MCSF), followed by three consecutive days of balance beam testing (PD [51][52][53]. After two rest days, the mice were trained on the Morris water maze (MWM) task from PD 56-63.…”

Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D

“…DYRK1A was also proved to phosphorylate Tau at Ser-202 and Ser-404 in both mammalian cells and DYRK1A transgenic mice, leading to disability of Tau to promote microtubule assembly 34 . Dyrk1A overexpression also leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice 35 . As DYRK1A is involved in Aβ production and Tau phosphorylation in AD pathology, elevated expression of DYRK1A by MEF2D might contribute to AD pathogenesis 23 , 36 .…”

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…Hyperphosphorylation of Tau can be influenced by dysregulation of alternative splicing of Tau reported in DS as well as in AD (Iqbal et al 2013). The dual-specificity tyrosine-phosphorylation-regulated kinase 1A ( DYRK1A ) gene and regulator of calcineurin 1 ( RCAN1 ) gene, are both located on Hsa21, both proteins are highly expressed in the DS brain, and have both been implicated in the dysregulation of Tau phosphorylation associated with early onset AD in DS (Yin et al 2017; Shi et al 2008). Interestingly, Dyrk1A-mediated phosphorylation of RCAN1 induces a targeted phosphorylation cascade that leads to Tau phosphorylation (Jung et al 2011).…”