Keywords

Down syndrome, Alzheimer's disease, Mouse genetic models, Brain abnormalities, Cognitive deficits, Mental disability, DYRK1A inhibitors, DYRK1A therapeutic target

Introduction

Trisomy of human chromosome 21 or Down syndrome is the most common genetic disease, with an incidence of 1/700 live births, characterized by various developmental defects including congenital heart disease, cranio-facial abnormalities, learning and memory deficits, cognitive impairments, mental retardation and the early onset of Alzheimer's disease. The neurological features and particularly the mental disability remains the invariable hallmark of Down syndrome and its more invalidating pathological aspect with a hard impact in the public health. This neurocognitive and genetic disorder is mainly a consequence of functional and developmental brain alterations, in neurogenesis, neuronal differentiation, myelination, dendritogenesis and synaptogenesis [1-3].

Clinical, cytogenetic and molecular studies allowed narrowing a critical triplicated region of human chromosome 21 called Down Syndrome Chromosomal Region or Down Syndrome Critical Region (DSCR) on the distal part of the long arm, around the marker D21S55 and flanked by D21S17 and ERG. The extra copy of DSCR is also associated with the expression of similar various developmental features of Down syndrome including the similar various neurological features. Consequently, the major phenotypes in Down syndrome patients and in mouse models, particularly the neurological phenotypes and mental disability, have their origin in the over-dosage of genes localized in the Down syndrome Chromosomal Region(DSCR) [4-7].

Gene expression profiling provides two kinds of research to understand the molecular basis of brain alterations and mental disability pathogenesis in Down syndrome [8,9]. On one hand, these investigations allowed the identification of genes specifically expressed in the brain and, on the other hand, the genes restricted to the key brain regions involved in the cognitive functions that we have selected and studied as critical candidate genes for neuronal abnormalities and mental disability [10-14]. The majority of trisomic or triplicated genes showed transcript levels increase of about 1.5 fold in human trisomic tissues [15,16] and in trisomic mouse models [17-19]. Particularly, in trisomic tissues, although most of the trisomic genes show transcriptional variations on average 1.5 fold the normal level, only a subset of candidate genes show a significant difference of expression level between trisomic and diploid individuals [19,20].

Two types of murine models of Down syndrome have been developed for investigating the molecular genetics of Down syndrome, the trisomic and the transgenic mouse models that represent powerful tools to study the kinetics of developmental phenotypes and the molecular and cellular basis of functional brain alterations seen in Down syndrome. The trisomic mouse models carrying segmental trisomy for mouse chromosome 16 (Ts65Dn and Ts1Cje), contains the orthologous conserved chromosomal regions of the most part of human chromosome 21q, including also the Down Syndrome Critical Region (DSCR), and mimic the same evolutionarily conserved interactions between different homologous genes present at 3 copies. These mouse models have similar clinical phenotypes seen in Down syndrome and facilitate our previous and recent investigations for identification, characterization and comparative analyses of similar critical candidate genes and their similar associated molecular pathways involved in similar neurological alterations including brain aberrations, cognitive impairments, learning and memory deficits seen in Down syndrome patients [21,22].

The transgenic mouse models of Down syndrome are also of the most interest because they have been generated to study the effect of cell-specific and stage-specific over expression of a unique critical gene and associated molecular pathway [22,23]. Among the critical genes, localized in the critical region DSCR, that we have determined specific and restricted expressions in the key brain regions involved in cognitive and learning-memory functions similarly in Down syndrome patients and in related Down syndrome mouse models, we have identified and studied herein DYRK1A as a master regulatory protein involved in developmental and functional brain alterations, cognitive impairments, learning-memory deficits, mental disability, as a key contributor to neurodegenerative disorders of Alzheimer's disease and as a promising potential drug target for multiple Down syndrome and Alzheimer's disease neuropathology opening news directions for developing new preventive and therapeutic treatments of Down syndrome and Alzheimer's disease [22,23].

Results and Discussion

Dual-Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A), well-known as Drosophila Mini-Brain gene (MNB), maps to 21q22.2 in Down Syndrome Critical Region (DSCR) and encodes a proline-directed Serine/Threonine kinase [24-26] involved in functional and developmental brain alterations, in neurogenesis,in neuronal differentiation, in neuronal proliferation, in neuritogenesis, in dendritogenesis, in synaptogenesis,in cognitive impairments, in learning and memory deficits and mental disability seen in Down syndrome [22,23].

DYRK1A is one powerful member of phosphorylation pathways that regulate the cell cycle and belongs to a family of Dual-Specificity Protein Kinases (DYRK kinases) with Serine/Threonine phosphorylation activity that contribute in several critical signaling pathways controlling various cellular processes, cell survival, cell proliferation, cell differentiation and have a key role in central nervous system [27,28]. DYRK1A phosphorylates numerous important transcriptional factors, such as endocytic proteins, cyclic AMP response element-binding protein (CREB), fork head in rhabdomyosarcoma (FKHR), or nuclear factor of activated T cells (NFATc) [29-34]. DYRK1A over expression was associated with an increase in the phosphorylation of fork head transcription factor FKHR and with high levels of cyclin B1, suggesting a significant association between DYRK1A over expression and cell cycle protein alteration [32].

Interestingly, DYRK1A is expressed in the key neuronal regions altered in Down syndrome brain patients [24,35] and is implicated in the neuronal differentiation of hippocampal progenitor cells through the phosphorylation of cyclic AMP response element-binding protein (CREB) [29,31]. In addition, the altered phosphorylation of transcription factor CREB supports an important role of DYRK1A over expression in the neuronal abnormalities seen in DS and indicates that this pathology is associated to altered levels of proteins involved in the regulation of cell cycle [36]. Altogether, these results suggest a central role of DYRK1A in the pathways of cell cycle control and the DYRK1A over expression contribute to neurogenesis alteration in the brain of Down syndrome patients [23].

In addition, DYRK1A phosphorylates also several endocytic proteins, such as dynamin 1 and amphiphysin 1 and consequently regulates the assembly of endocytic complexes, endophilin 1 and Grb2, suggesting that DYRK1A is strongly associated with the endocytic pathway [33,34]. Furthermore, the expression of DYRK1A associates cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling [37]. The up regulation of DYRK1A contribute also to altered neuronal proliferation in the brain of Down syndrome patients through the specific phosphorylation of p53 and inhibition of proliferation of embryonic neuronal cells [38].

The DYRK1A over expression combined with the over expression of DSCR1,dysregulates the nuclear factor of activated T cells NFAT pathway that play a critical role in the central nervous system anddemonstrates a functional interaction between two critical genes in Down Syndrome Critical Region (DSCR) explaining a molecular mechanism involved in DS phenotypes [30]. This molecular mechanism demonstrated by a cooperative and functional interaction between the critical genes DYRK1A and DSCR1 provides an important view of a molecular mechanism in accordance with our previous proposed molecular and cellular mechanisms [8,22,23] elucidating a functional association between dysregulation in critical chromosome 21 genes and related molecular pathways, brain alterations and related mental disability, and suggesting also a critical role of DYRK1A dosage-sensitive gene in the central nervous system and in neurocognitive and functional impairments associated with brain alteations and the pathogenesis of mental disability in Down syndrome [8,22,23]. Overall, and in addition to its key role as a member of DYRK kinases, all these results suggest that DYRK1A is widely involved in various cellular events and contribute significantly in several critical signaling pathways that control important neuronal processes, proliferation and differentiation, cell cycle and neurogenesis in Down syndrome.

The transgenic mouse models over expressing DYRK1A showed neurodevelopment delay, motor abnormalities and cognitive deficits with significant impairments in spatial learning and memory, indicating hippocampal and prefrontal cortex function alterations, comparable with those found in trisomic mouse models of Down syndrome, and suggesting a causative role of DYRK1A in neurological and functional brain alterations and mental disability seen in Down syndrome patients [39-41]. The genetic reductions of DYRK1A copy number in trisomic mouse models of DS revealed important corrections of Down syndrome phenotypes and showed important improvements in cognitive and behavioural phenotypes [42,43].

Interestingly, the treatment of DYRK1A transgenic mouse models of Down syndrome with injection into striatum of inhibitory Dyrk1A shRNA restores the motor coordination, attenuates the hyperactivity and improves the sensorimotor gating, and the normalization of DYRK1A expression by AAV2/1-ShDyrk1A attenuates the hippocampal-dependent defects in Ts65Dn trisomicmouse models of Down syndrome, indicates DYRK1Aas a potential therapeutic target [44,45]. In addition, the treatment of DYRK1A transgenic mouse models of Down syndrome with an inhibitory DYRK1A, the epigalloctechin-3-gallate (EGCG), rescues the brain defects and restores the cognitive impairments induced by the over expression of DYRK1A and indicates DYRK1A as a therapeutic target in DYRK1A transgenic mouse models and in trisomic mouse models of Down syndrome and in human [46-48].

Remarkably, one of the major neuro-pathological features of Down syndrome is a sign of early onset of Alzheimer's disease-like symptoms, characterized by the formation of amyloid senile plaques (insoluble deposits of β-Amyloid) and of neurofibrillary tangles (hyperphosphorylated Tau aggregates) [49,50]. Interestingly, DYRK1A phosphorylates key substrates implicated in Alzheimer's disease such as Tau, Amyloid Precursor Protein (APP) andPresenilin 1 (PS1) and indicates an important role of DYRK1A in the onset of Alzheimer's disease [51-53].

DYRK1A phosphorylates several serine and threonine residues of Tau and the Tau hyperphosphorylation mediated by DYRK1A results both in the brain of Ts65Dn trisomic mouse models of Down syndrome as well as in the brain of Down syndrome patients. More interestingly, DYRK1A immunoreactivity in Tau positive neurofibrillary tangles in Down syndrome brains supports a significant association between DYRK1A and Tau and the contribution of DYRK1A over expression to neurofibrillary degeneration indicates a key role of over expressed DYRK1A protein in the early onset of neurofibrillary degeneration seen in the brain of Down syndrome patients [54,55]. The over expression of DYRK1A increases Tau expression and cognitive deficits in Ts65Dn trisomic mouse models of Down syndrome [56] and the hyperphosphorylation of Tau mediated by DYRK1A showed a functional association between Down syndrome and Alzheimer's disease [51].

Moreover, DYRK1A is significantly associated with the regulation of cytoskeletal protein such as actin, tubulin and microtubule-linked protein Tau through DYRK1A phosphorylation of many substrates that consequently contributes to the regulation of neuritogenesis, synaptogenesis, and Alzheimer's disease-like neurofibrillary tangles formation [57-60]. Remarkably, DYRK1A plays a role in β-amyloid production and senile plaques formation and phosphorylate the intracellular domain of Amyloid Precursor Protein (APP), for which the encoded gene APP is also mapped to human chromosome 21. Furthermore, the DYRK1A gene encoded in the chromosome 21 Down Syndrome Critical Region bridges between β-Amyloid production and Tau phosphorylation in Alzheimer's disease [61]. In addition, the phosphorylation of Amyloid Precursor Protein (APP) mediated by DYRK1A evidenced also a functional association between Down syndrome and Alzheimer's disease [52].

The normalization of DYRK1A dosage, by DYRK1A inhibitors, in mouse models of Down syndrome rescues also several Alzheimer's disease phenotypes indicating DYRK1A as a potent therapeutic target. In addition, DYRK1A inhibition improves Alzheimer's disease‐like pathology and the effect of DYRK1A inhibitors on Tau and amyloid pathologies confirmed well the DYRK1A inhibition as a potential and an effective treatment for Alzheimer's disease [62-65].

Interestingly, the treatment with an inhibitory DYRK1A, the epigallocatechin-3-gallate (EGCG), modulates also the amyloid precursor protein (APP) cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice [66]. The treatment by the inhibitor of DYRK1A, the Harmine, specifically and successfully inhibits the protein kinase DYRK1A activity and reduced Tau phosphorylation in neuroglioma cell line at multiple Alzheimer's disease-related sites [67]. The treatment by another inhibitor of DYRK1A, the Leucettine L41, effectively inhibits DYRK1A activity, rescues Alzheimer's disease phenotypes in APP/PS1 mice and corrects the cognition deficits and memory impairments in Alzheimer's disease animal models [68,69]. In addition, the treatment by an oral DYRK1A inhibitor, the SM07883, significantly inhibits Tau hyperphosphorylation, aggregation, neurofibrillary tangles formation, and associated Alzheimer's disease phenotypes in mouse models suggesting also this novel DYRK1A inhibitor as a potential treatment for Alzheimer's disease [70].

Conclusion

DYRK1A (Dual-specificity tyrosine phosphorylation-Regulated Kinase 1A) is one influential and key member of the phosphorylation pathways that regulate the cell cycle and belongs to a family of dual-specificity protein kinases (DYRK kinases) that play a critical role in central nervous system and in several crucial signaling pathways that control various cellular processes. In addition, DYRK1A regulates and phosphorylates also several important transcriptional factors, such as fork head (FKHR), cyclic AMP response element binding protein (CREB), endocytic proteins and nuclear factor of activated T cells (NFAT) and associated pathways that play critical roles in the central nervous system indicating a central role of DYRK1A in the brain development and function of trisomic and transgenic mouse models of Down syndrome and in the brain of Down syndrome patients.

The significant associations between DYRK1A and regulation of cytoskeletal dynamics of actin, tubulin or microtubule linked protein Tau, regulation of phosphorylation of Tau, Amyloid Precursor Protein (APP) or Presenilin 1 (PS1), regulation of neurogenesis, neuritogenesis, synaptogenesis, and Alzheimer's disease-like neurofibrillary tangles formation is of the most interest indicating DYRK1A as a potent candidate and a master regulatory protein involved in Down syndrome brain alterations, cognitive impairments, learning-memory deficits, mental disability, and a key contributor to neurodegenerative disorders of Alzheimer's disease.

Interestingly, the normalization of the gene dosage of DYRK1A in mouse models of Down syndrome rescues also several Alzheimer's disease phenotypes indicating DYRK1A as potent therapeutic target and the effect of DYRK1A inhibitors on Tau and amyloid pathologies confirmed well the DYRK1A inhibition as a potential and an effective treatment for Down syndrome and Alzheimer's disease.

The DYRK1A inhibitors such as the epigalloctechin-3-gallate (EGCG)specifically inhibits the protein kinase DYRK1A activity, rescues the brain defects and restores the cognitive impairments in DYRK1A transgenic mouse models and in trisomic mouse models of Down syndrome and in Down syndrome patients. Moreover, the epigallocatechin-3-gallate (EGCG) modulates also the Amyloid Precursor Protein (APP) cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.The DYRK1A inhibitors such as the Harmine, LeucettineL41 and SM07883 successfully reduces Tau phosphorylation at multiple Alzheimer's disease-related sites and rescues Alzheimer phenotypes in APP/PS1 mice and correct the cognition deficits and memory impairments in Alzheimer's disease animal models indicating these DYRK1A inhibitors as active inhibitors and potential therapeutics for Down syndrome and Alzheimer's disease.

Overall, these results indicate DYRK1A as a promising potential drug target for multiple Down syndrome and Alzheimer's disease neuropathology opening news directions for developing new preventive and therapeutic treatments of Down syndrome and Alzheimer's disease.

References

1. Korenberg JR, Chen XN, Schipper R, Sun Z, Gonsky R, et al. (1994) Down syndrome phenotypes: The consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91: 4997-5001.
2. Rachidi M, Lopes C (2007) Molecular mechanisms of mental retardation in down syndrome. In: Carson MI, Focus on mental retardation research, Nova Science Publishers, 77-134.
3. Rachidi M, Lopes C (2008) Molecular mechanisms of mental retardation in down syndrome. In: Rachidi M, Lopes C, Nova Biomedical Book, Nova Science Publishers, 1-94.
4. Rahmani Z, Blouin JL, Creau-Goldberg N, Watkins PC, Mattei JF, et al. (1989) Critical role of the D21S55 region on chromosome 21 in the pathogenesis of down syndrome. Proc Natl Acad Sci USA 86: 5958-5962.
5. McCormick MK, S chinzel A, Petersen MB, Stetten G, Driscoll DJ, et al. (1989) Molecular genetics approach to the characterization of the “down syndrome region” of chromosome 21. Genomics 5: 325-331.
6. Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, et al. (1990) Molecular definition of a region of chromosome 21 that causes features of the down syndrome phenotype. Am J Hum Genet 47: 236-246.
7. Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, et al. (2009) The “Down Syndrome Critical Region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of down syndrome. J Neurosci 29: 5938-5948.
8. Rachidi M, Lopes C (2007) Mental retardation in down syndrome: From gene dosage imbalance to molecular and cellular mechanisms. Neurosci Res 59: 349-369.
9. Rachidi M, Lopes C (2009) Gene expression regulation in down syndrome: Dosage imbalance effects at transcriptome and proteome levels. Handbook of Down Syndrome Research: Nova Science Publishers, 55-87.
10. Rachidi M, Lopes C, Gassanova S, Sinet PM, Vekemans M, et al. (2000) Regional and cellular specificity of the expression of TPRD, the tetratricopeptide down syndrome gene, during human embryonic development. Mech Deve 93: 189-193.
11. Rachidi M, Lopes C, Costantine M, Delabar JM (2005) C21orf5, a new member of dopey family involved in morphogenesis, could participate in neurological alterations and mental retardation in down syndrome. DNA Res 12: 203-210.
12. Rachidi M, Lopes C, Charron G, Delezoide AL, Paly E, et al. (2005) Spatial and temporal localization during embryonic and fetal human development of the transcription factor SIM2 in brain regions altered in down syndrome. Int J Dev Neurosci 23: 475-484.
13. Rachidi M, Delezoide AL, Delabar JM, Lopes C (2009) A quantitative assessment of gene expression (QAGE) reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in down syndrome brain regions. Int J Dev Neurosci 27: 393-398.
14. Reymond A, Marigo V, Yaylaoglu MB, Leoni A, Ucla C, et al. (2002) Human chromosome 21 gene expression atlas in the mouse. Nature 420: 582-586.
15. FitzPatrick DR, Ramsay J, McGill NI, Shade M, Carothers AD, et al. (2002) Transcriptome analysis of human autosomal trisomy. Hum Mol Genet 11: 3249-3256.
16. Mao R, Zielke CL, Zielke HR, Pevsner J (2003) Global up-regulation of chromosome 21 gene expression in the developing down syndrome brain. Genomics 81: 457-467.
17. Lyle R, Gehrig C, Neergaard-Henrichsen C, Deutsch S, Antonarakis SE (2004) Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res 14: 1268-1274.
18. Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, et al. (2004) Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res 14: 1258-1267.
19. Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, et al. (2007) Gene expression variation in down's syndrome mice allows prioritization of candidate genes. Genome Biol 8: R91.
20. Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, et al. (2007) Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet 81: 252-263.
21. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, et al. (1995) A mouse model for down syndrome exhibits learning and behavior deficits. Nat Genet 11: 177-184.
22. Rachidi M, Lopes C (2008) Mental retardation and associated neurological dysfunctions in down syndrome: A consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways. Eur J Paediatr Neurol 12: 168-182.
23. Rachidi M, Lopes C (2010) Molecular and cellular mechanisms elucidating the neurocognitive basis of functional impairments associated with intellectual disability in down syndrome. Am J Intellect Dev Disabil 115: 83-112.
24. Guimera J, Casas C, Pucharcos C, Solans A, Domenech A, et al. (1996) A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in down syndrome and maps to the critical region. Hum Mol Genet 5: 1305-1310.
25. Song WJ, Sternberg LR, Kasten-Sportes C, Keuren MLV, Chung SH, et al. (1996) Isolation of human and murine homologues of the Drosophila mini-brain gene: Human homologue maps to 21q22.2 in the down syndrome "critical region". Genomics 38: 331-339.
26. Himpel S, Tegge W, Frank R, Leder S, Joost HG, et al. (2000) Specificity determinants of substrate recognition by the protein kinase DYRK1A. J Biol Chem 275: 2431-2438.
27. Lochhead PA, Sibbet G, Morrice N, Cleghon V(2005) Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell 121: 925-936.
28. Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach A, et al. (2013) Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure 21: 986-996.
29. Yang EJ, Ahn YS, Chung KC (2001) Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J Biol Chem 276: 39819-39824.
30. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, et al. (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441: 595-600.
31. Gwack Y, Sharma S, Nardone J,Tanasa B, Iuga A, et al. (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646-650.
32. Woods YL, Rena G, Morrice N, Barthel A, Becker W, et al. (2001) The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J 355: 597-607.
33. Chen-Hwang MC, Chen HR, Elzinga M, Hwang YW (2002) Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. J Biol Chem 277: 17597-17604.
34. Murakami N, Xie W, Lu RC, Chen-Hwang MC, Wieraszko A, et al. (2006) Phosphorylation of Amphiphysin I by Minibrain kinase/Dual-specificity tyrosine phosphorylation-regulated kinase, a kinase implicated in down syndrome. J Biol Chem 281: 23712-23724.
35. Rahmani Z, Lopes C, Rachidi M, Delabar JM. (1998) Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues. Biochem Biophys Res Commun 253: 514-518.
36. Branchi I, Bichler Z, Minghetti L, Delabar JM, Malchiodi-Albedi F, et al. (2004) Transgenic mouse in vivo library of human down syndorme Critical Region 1: Association between DYRK1A over expression, brain development abnormalities, and cell cycle protein alteration. J Neuropathol Exp Neurol 63: 429-440.
37. Hammerle B, Ulin E, Guimera J, Becker W, Guillemot F, et al. (2011) Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling. Development 138: 2543-2554.
38. Park J, Oh Y, Yoo L, Jung MS, Song WJ, et al. (2010) Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal Cells. J Biol Chem 285: 31895-31906.
39. Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, et al. (2001) Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of down's syndrome. Hum Mol Genet 10: 1915-1923.
40. Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, et al. (1997) Functional screening of 2Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with down syndrome. Nat Genet 16: 28-36.
41. Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, et al. (2006) DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis 22: 463-472.
42. Blazek JD, Abeysekera I, Li J, Roper RJ (2015) Rescue of the abnormal skeletal phenotype in Ts65Dn down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a. Hum Mol Genet 24: 5687-5696.
43. Nguyen TL, Duchon A, Manousopoulou A, Loaëc N, Villiers B, et al. (2018) Correction of cognitive deficits in mouse models of down syndrome by a pharmacological inhibitor of DYRK1A. Dis Model Mech 11.
44. Ortiz-Abalia J, Sahun I, Altafaj X, Andreu N, Estivill X, et al. (2008) Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of down syndrome. Am J Hum Genet 83: 479-488.
45. Altafaj X, Martin ED, Ortiz-Abalia J, Valderrama A, Lao-Peregrin C, et al. (2013) Normalization of Dyrk1A expression by AAV2/1-ShDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn Mouse Model of down syndrome. Neurobiol Dis 52: 117-127.
46. Guedj F, Sebrie C, Rivals I, Ledru A, Paly E et al. (2009) Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PloS One 4: e4606.
47. De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, et al. (2014) Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in down syndrome mouse models and in humans. Mol Nutr Food Res 58: 278-288.
48. McElyea SD, Starbuck JM, Brink DT, Harrington E, Blazek JD, et al. (2016) Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with down syndrome. Hum Mol Genet 25: 4856-4869.
49. Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in down’s syndrome. Ann Neurol 17: 278-282.
50. Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, et al. (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in down’s syndrome. Nat Med 2: 93-95.
51. Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, et al. (2007) DYRK1A-mediated hyperphosphorylation of Tau. A functional link between down syndrome and Alzheimer disease. J Biol Chem 282: 34850-34857.
52. Ryoo SR, Cho HJ, Lee HW, Jeong HK, Radnaabazar C, et al. (2008) Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: Evidence for a functional link between down syndrome and Alzheimer’s disease. J Neurochem 104: 1333-1344.
53. Ryu YS, Park SY, Jung MS, Yoon SH, Kwen MY, et al. (2010) Dyrk1A-mediated phosphorylation of presenilin 1: A functional link between down syndrome and Alzheimer’s Disease. J Neurochem 115: 574-584.
54. Liu F, Liang Z, Wegiel J, Hwang YW, Iqbal K, et al. (2008) Over expression of Dyrk1A contributes to neurofibrillary degeneration in down syndrome. FASEB J 22: 3224-3233.
55. Wegiel J, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, et al. (2008) The role of over expressed DYRK1A protein in the early onset of neurofibrillary degeneration in down syndrome. Acta Neuropathol 116: 391-407.
56. Yin X, Jin N, Shi J, Zhang Y, Wu Y, et al. (2017) Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn down syndrome mice. Sci Rep 7: 619.
57. Martinez de Lagran M, Benavides-Piccione R, Ballesteros-Yanez I, Calvo M, Morales M, et al. (2012) Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. Cereb Cortex 22: 2867-2877.
58. Scales TM, Lin S, Kraus M, Goold RG, Gordon-Weeks PR (2009) Nonprimed and DYRK1A-primed GSK3 beta-phosphorylation sites on MAP1B regulate microtubule dynamics in growing axons. J Cell Sci 122: 2424-2435.
59. Park J, Sung JY, Park J, Song WJ, Chang S, et al. (2012) Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP. J Cell Sci 125: 67-80.
60. Dowjat K, Adayev T, Kaczmarski W, Wegiel J, Hwang YW (2012) Gene dosage-dependent association of DYRK1A with the cytoskeleton in the brain and lymphocytes of down syndrome patients. J Neuropathol Exp Neurol 71: 1100-1112.
61. Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, et al. (2007) The DYRK1A gene, encoded in chromosome 21 down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer Disease. Hum Mol Genet 16: 15-23.
62. Branca C, Shaw DM, Belfiore R, Gokhale V, Shaw AY, et al. (2017) Dyrk1 inhibition improves Alzheimer's disease‐like pathology. Aging Cell 16: 1146-1154.
63. Garcia‐Cerro S, Rueda N, Vidal V, Lantigua S, Martinez‐Cue C (2017) Normalizing the gene dosage of Dyrk1A in a mouse model of down syndrome rescues several Alzheimer's disease phenotypes. Neurobiol Dis 106: 76-88.
64. Coutadeur S, Benyamine H, Delalonde L, de Oliveira C, Leblond B, et al. (2015) A novel DYRK1A (dual specificity tyrosine phosphorylation‐regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: Effect on Tau and amyloid pathologies in vitro. J Neurochem 133: 440-451.
65. Stotani S, Giordanetto F, Medda F (2016) DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem 8: 681-696.
66. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, et al. (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25: 8807-8814.
67. Frost D, Meechoovet B, Wang T, Gately S, Giorgetti M, et al. (2011) β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS One 6: e19264.
68. Souchet B, Audrain M, Billard JM, Dairou J, Fol R, et al. (2019) Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice. Acta Neuropathol Commun 7: 46.
69. Naert G, Ferre V, Meunier J, Keller E, Malmstrom S, et al. (2015) Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice. Eur Neuropsychopharmacol 25: 2170-2182.
70. Melchior B, Mittapalli GK, Lai C, Duong‐Polk K, Stewart J (2019) Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease. Aging Cell 18: e13000.

---